Bicyclic pyrazole compounds as antibacterial agents

ABSTRACT

Antibacterial compounds, compositions containing them, and methods of use for the inhibition of bacterial activity and the treatment, prevention or inhibition of bacterial infection.

This application is a divisional of U.S. patent application Ser. No.11/393,558, filed on Mar. 30, 2006, now U.S. Pat No. 7,842,810 which inturn claims the benefit of U.S. provisional patent application Ser. No.60/667,198, filed on Mar. 31, 2005, each of which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

This invention relates to heterocyclic compounds, more particularlypyrazole compounds, compositions containing them, and methods of usingthem as antibacterial agents.

BACKGROUND OF THE INVENTION

The chemical and medical literature describes compounds that areantimicrobial, i.e., capable of destroying or suppressing the growth orreproduction of microorganisms, such as bacteria. For example, suchantibacterial agents are described in Antibiotics, Chemotherapeutics,and Antibacterial Agents for Disease Control (M. Greyson, ed., 1982),The Molecular Basis of Antibiotic Action, 2d ed. (E. Gale, et al.,1981), Recent Research Developments in Antimicrobial Agents &Chemotherapy (S. G. Pandalai, ed., 2001), Quinolone Antimicrobial Agents(J. S. Wolfson, D. C. Hooper, eds., 1989), and Antibiotics andChemotherapy, 7th edn. (F. O'Grady, H. P. Lambert, R. G. Finch, D.Greenwood, M. Dedicoat, 1997).

The mechanisms of action of these antibacterial agents vary. However,they may function in one or more ways including: by inhibiting cell wallsynthesis or repair; by altering cell wall or membrane permeability; byinhibiting or altering protein synthesis; by inhibiting the synthesis ofnucleic acids or by inhibition of folate metabolism. For example,beta-lactam antibacterial agents act through inhibiting essentialpenicillin binding proteins (PBPs) in bacteria, which are essential forcell wall synthesis. As another example, quinolones act, at least inpart by inhibiting synthesis of DNA, thus preventing the cell fromreplicating.

The pharmacological characteristics of antimicrobial agents, and theirsuitability for any given clinical use, vary. For example, the classesof antimicrobial agents (and members within a class) may vary in 1)their relative efficacy against different types of microorganisms, 2)their frequency and rate of development of microbial resistance and 3)their pharmacological characteristics, such as their bioavailability andbiodistribution. Accordingly, selection of an appropriate antimicrobialagent in a given clinical situation requires analysis of many factors,including the type of organism involved, the desired method ofadministration, the location of the infection to be treated and otherconsiderations.

However, many such attempts to produce improved antimicrobial agentsyield equivocal results. Indeed, few antimicrobial agents have beenproduced that are truly clinically acceptable in terms of their spectrumof antimicrobial activity, avoidance of microbial resistance,pharmacology, and toxicology. Thus, there is a continuing need forantimicrobial agents that are effective against resistant microbes. Thisneed has been highlighted in the relevant literature. See, for example,C. F. Amábile-Cuevas, “New Antibiotics and New Resistance”, AmericanScientist, vol. 91, 138-149 (March-April 2003) (noting that for nearlytwenty years, until the late 1990s, “not a single truly new antibioticwas introduced into clinical use”, while “resistance keeps evolving, anddrugs are rapidly losing their efficacy, resulting in increasedtreatment costs, loss of labor time and, of course worst of all, lostlives.”).

Examples of bacterial infections resistant to antibiotic therapy havebeen reported in the past; they are now a significant threat to publichealth. For example, methicillin-resistant Staphylococcus aureus (MRSA)is a type of bacterium that is resistant to certain antibiotics. Theseantibiotics include methicillin, amoxicillin, and ciprofloxacin.Staphylococcus infections, such as those with MRSA, have a plurality oforigins. They occur most frequently among persons in hospitals andhealthcare facilities, such as nursing homes and dialysis centers, whohave weakened immune systems. These infections, however, are not limitedto exposure to the environment in healthcare facilities or medicalprocedures such as dialysis, surgery, and catheters, but they are alsoacquired by the population at large, hence the term community-associatedMRSA. The development of microbial resistance (perhaps as a result ofthe extensive use of antibacterial agents) is of increasing concern inmedical science. “Resistance” can be defined as the existence oforganisms, within a population of a given microbial species, that areconsiderably less susceptible to the action of a given antimicrobialagent. This resistance is of particular concern in environments such ashospitals and nursing homes, where relatively high rates of infectionand extensive use of antibacterial agents are common. See, e.g., W.Sanders, Jr., et al., “Inducible Beta-lactamases: Clinical andEpidemiologic Implications for the Use of Newer Cephalosporins”, Reviewof Infectious Diseases, p. 830 (1988).

Pathogenic bacteria are known to acquire resistance via several distinctmechanisms including inactivation of the antibiotic by bacterial enzymes(e.g., β-lactamases hydrolyzing penicillin and cephalosporins), whetherthese enzymes are encoded by genes native to the organism or encoded bygenes acquired through transfer from an external source (e.g.,methicillin-resistance in Staphylococcus aureus); removal of theantibiotic using efflux pumps; modification of the target of theantibiotic via mutation and genetic recombination (e.g.,penicillin-resistance in Neiserria gonorrhoeae). There are certainGram-positive pathogens, such as vancomycin-resistant Enterococcusfaecium, which are resistant to virtually all commercially availableantibiotics.

Hence existing antibacterial agents have limited capacity in overcomingthe threat of resistance. Thus it would be advantageous to provide newantibacterial agents that can be used against resistant microbes.

The present invention includes pyrazole compounds and derivativesthereof; the use of said pyrazole compounds as inhibitors of bacterialgrowth; their use for the treatment of bacterial infection; and thepreparation of pharmaceutical compositions for the treatment ofbacterial infection. Compounds according to the present invention andderivatives thereof can also be used as reference compounds in assays toassess antibacterial characteristics in light of one or more factorsconcerning bacterial activity, such as bacterial growth inhibition,toxicity, bioavailability, and protein binding capability.

SUMMARY OF THE INVENTION

There are provided by the present invention compounds that have thefollowing general formula (I):

where said formula (I) has a B-containing bicyclic ring system

and a fused pyrazole moiety

wherein

-   each of B¹, B⁵, and B⁸ is independently CR^(a) or N, wherein not all    three B¹, B⁵, and B⁸ are N;-   each of R^(a), R², R³, R⁶ and R⁷ is independently selected from the    group consisting of —H, —C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,    —C₃₋₆cycloalkyl, —OR^(b), —NR^(c)R^(d), —O(CH₂)₂₋₃NR^(c)R^(d),    —SR^(b), —S(O)R^(b), —SO₂R^(b), cyano, —CF₃, halo, —NO₂, —OCF₃,    —C(O)R^(b), —OC(O)R^(b), —C(O)NR^(c)R^(d), and —CO₂R^(b); wherein    each of R^(b), R^(c) and R^(d) is independently selected from the    group consisting of —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl, and    —C₁₋₂alkyl(C₃₋₆cycloalkyl)-; and wherein each alkyl or cycloalkyl    moiety in any of R^(a), R², R³, R⁶, R⁷, R^(b), R^(c), and R^(d) is    optionally and independently substituted with one, two or three    substituents selected from —C₁₋₃alkyl, halo, hydroxy, amino, and    —C₁₋₃alkoxy;-   the B-containing bicyclic ring system is attached at the 1- or    2-position of the fused pyrazole moiety;-   m is 0 or 1;-   n is 1 or 2, wherein m+n is 2 or 3;-   X is CH or N;-   provided that when X is N, then Y is —C(O)—, —CH₂C(O)—, or    —(CH₂)₂₋₃O— optionally substituted with —C₁₋₃alkyl;-   and when X is CH, then Y is —N(R^(e))Z—;-   Z is selected from the group consisting of: C₁₋₃alkylene optionally    substituted with —C₁₋₃alkyl; C₃alkenylene optionally substituted    with —C₁₋₃alkyl; —C(O)C₂alkenyl- optionally substituted with    —C₁₋₃alkyl; —(CH₂)₀₋₁C(O)—; —CH₂C(O)N(R^(f))(CH₂)₀₋₁—; —(CH₂)₂₋₃O—;    and —C(O)C(R^(g1))(R^(g2))—;    -   where R^(e) is —H, —C₁₋₄alkyl, benzyl, —C(O)C₁₋₆alkyl,        —C(O)phenyl, —C(O)benzyl, —C₁₋₆alkylCO₂C₁₋₆alkyl, or        —C₁₋₆alkylCO₂H;    -   R^(f) is —H or —C₁₋₄alkyl; and    -   each of R^(g1) and R^(g2) is independently —H or methyl, or        R^(g1) and R^(g2) are taken together with their carbon of        attachment to form a C₃₋₇cycloalkyl, or the group        C(R^(g1))(R^(g2)) is the group C═O;-   A is an aryl or heteroaryl ring selected from the group consisting    of:    -   a) unsubstituted phenyl, unsubstituted pyridyl, substituted        phenyl, and substituted pyridyl, wherein said substituted phenyl        is moiety (M1) or moiety (M2)

-   -   and said substituted pyridyl is moiety (M3) or moiety (M4)

-   -   wherein R^(r) _((p-q)) stands for a number of R^(r) substituents        that is at least p and does not exceed q, and

-   -    is a disubstituent at two adjacent carbon members, said        disubstituent being selected from the group consisting of        —O—C14AL-O—, —N(R^(h))(CH₂)₂₋₃S—, —N(R^(h))C(O)(CH₂)₁₋₂S—,        —N(R^(h))C(O)C(CH₃)₂S—, —N(R^(h))(CH₂)₂₋₃O—,        —N(R^(h))C(O)(CH₂)₁₋₂O—, —N(R^(h))(CH₂)₂₋₃NH—, and        —N(R^(h))C(O)(CH₂)₁₋₂NH—, wherein said C14AL is a C₁₋₄alkylene        optionally mono- or di-substituted with F,        -   where each —R^(r) is independently selected from the group            consisting of —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₂₋₆alkenyl,            —OC₃₋₆alkenyl, —C₂₋₆alkynyl, —OC₃₋₆alkynyl, —CN, —NO₂,            —N(R^(y))R^(z), —C(O)N(R^(y))R^(z), —N(R^(t))C(O)R^(t),            —N(R^(t))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —SC₁₋₆alkyl,            —SO₂C₁₋₆alkyl, —SO₂N(R^(y))R^(z), halo, —CF₃, —OCF₃, —CO₂H            and —CO₂C₁₋₆alkyl;            -   wherein R^(t) is —H or —C₁₋₆alkyl;        -   R^(y) and R^(z) are independently selected from —H and            —C₁₋₆alkyl, or R^(y) and R^(z) are taken together with their            nitrogen of attachment to form pyrrolidinyl or piperidinyl;            and        -   R^(h) is selected from the group consisting of —H,            —C₁₋₆alkyl, —C₁₋₆alkylCO₂H, —C₁₋₆alkylCO₂C₁₋₆alkyl, and            benzyl;    -   b) a five-membered monocyclic heteroaromatic group having a        carbon member which is the point of attachment, having one        hetero-member that is >O, >S, >NH, or >N(C₁₋₄alkyl), having up        to one additional hetero-member that is —N═, said five-membered        monocyclic heteroaromatic group being optionally mono- or        di-substituted with R^(r) and optionally benzofused or        pyridofused, where the benzofused or pyridofused moiety is        optionally mono-, di-, or tri-substituted with R^(r); and    -   c) a six-membered monocyclic heteroaromatic group having a        carbon member which is the point of attachment, having two        hetero-members each being —N═, said six-membered monocyclic        heteroaromatic group being optionally mono- or di-substituted        with R^(r) and optionally benzofused or pyridofused, where the        benzofused or pyridofused moiety is optionally mono- or        di-substituted with R^(r);        and isomers, racemates, tautomers, hydrates, solvates, and        pharmaceutically acceptable salts, esters, and amides thereof.

The “(p-q)” notation used with moieties (M1)-(M4) indicates that moiety(M1) has from one to five independently selected substituents R^(r).Moiety (M3) has from one to four independently selected substituentsR^(r). Independently selected substituents R^(r) in moiety (M2) range innumber from zero to three, and independently selected substituents R^(r)in moiety (M4) range in number from zero to two.

It has been found that the compounds of this invention, and compositionscontaining these compounds have antibacterial activities against a rangeof pathogenic microorganisms with advantages of activity againstresistant bacterial strains.

Accordingly, the present invention is also directed to a method oftreating a subject having a condition caused by or contributed to bybacterial infection, which comprises administering to said subject atherapeutically effective amount of at least one compound of Formula(I), and/or derivative thereof.

The present invention is further directed to a method of preventing asubject from suffering from a condition caused by or contributed to bybacterial infection, which comprises administering to the subject aprophylactically effective amount of at least one compound of Formula(I), and/or derivative thereof.

Embodiments of compounds of formula (I) are antibacterial agents.Embodiments of this invention comprise mixtures of compounds of formula(I).

Isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, amides and esters, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example, in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture. Compounds according to this invention may also exist, forexample, in a single atropisomeric form or as a mixture of atropisomers.Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the rotational barrier is high enough to allow forconformer isolation. See, for example, E. L. Eliel and S. H. Wilen,Stereochemistry of Organic Compounds, Ch. 14, Wiley & Sons, New york(1994), and M. Õki, Top. Stereochem. Vol. 14, 1-81 (1984).

Whether stated explicitly or not in any part of the written descriptionand claims, it is understood that each substituent and member assignmentin the context of this invention is made independently of any othermember and substituent assignment, unless stated otherwise. By way of afirst example on substituent terminology, if substituent S¹ _(example)is one of S₁ and S₂, and substituent S² _(example) is one of S₃ and S₄,then these assignments refer to embodiments of this invention givenaccording to the choices S¹ example is S₁ and S² _(example) is S₃; S¹_(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ and S²_(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent R assignments described herein. The foregoing conventiongiven herein for substituents extends, when applicable, to members suchas X and Z, and to any index if applicable.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁, S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent R assignments described herein. The foregoing conventiongiven herein for substituents extends, when applicable, to members suchas X and Z, and to any index if applicable.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to j,including i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

When any variable referring to a substituent, compound member, or indexoccurs more than once, the full range of assignments is meant to applyto each occurrence, independently of the specific assignment(s) to anyother occurrence of such variable. For each occurrence of a variable, itis understood that such an assignment is made independently from othermember and substituent assignments.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

The present invention also features methods for inhibiting bacterialactivity with such compounds, pharmaceutical compositions containingsuch compounds, and methods of using such compositions in the treatmentor prevention of conditions that are mediated by bacterial activity,such as infection.

Pharmaceutical compositions according to the present invention includeat least one of the compounds of the present invention. If more than oneof such compounds is included in a composition, the therapeuticallyeffective amount may be a jointly effective amount. As such inhibitorsof bacterial activity, compounds and compositions according to thepresent invention are useful in the prevention, inhibition, or treatmentof bacterial infection.

The invention also features a pharmaceutical composition for treating orpreventing bacterial infection in a subject, comprising atherapeutically effective amount of at least one antibacterial agentselected from compounds of formula (I), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof. In addition, the inventionfeatures a pharmaceutical composition for inhibiting bacterial activityor infection in a subject, comprising a therapeutically effective amountof at least one antibacterial agent selected from compounds of formula(I), enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof. The invention additionally features an antibacterial oranti-infective composition, comprising a therapeutically effectiveamount of at least one antibacterial compound selected from compounds offormula (I), enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof.

The invention also features methods for treating or preventing abacteria-mediated condition or bacterial infection in a subject,comprising administering to the subject a pharmaceutical compositionthat comprises a therapeutically effective amount of at least oneantibacterial agent selected from compounds of formula (I), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof.Furthermore, the invention features methods for inhibiting bacterialactivity in a subject, comprising administering to the subject apharmaceutical composition that comprises a therapeutically effectiveamount of at least one antibacterial agent selected from compounds offormula (I), enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof.

This invention features methods for the treatment, prevention and/orinhibition of conditions that are associated with and/or cause bacterialinfection. Subjects on which such methods are implemented are notlimited by the nature of the host.

Additional features and advantages of the invention will become apparentfrom the detailed description below, including examples, and theappended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I), as hereindefined, enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof, pharmaceutical compositions that contain at least one of suchcompounds, methods of using, including treatment and/or prevention ofconditions such as those that are mediated by bacterial activity, andmethods of making such pharmaceutical compositions.

The following terms are defined below, and by their usage throughout thedisclosure.

“Alkyl” includes straight chain and branched hydrocarbons with at leastone hydrogen removed to form a radical group. Alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, andso on. Alkyl does not include cycloalkyl.

“Alkenyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon double bond (sp²). Unlessindicated otherwise by the prefix that indicates the number of carbonmembers, alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl(or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl,butadienyls, pentenyls, hexa-2,4-dienyl, and so on.

“Alkynyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon triple bond (sp). Unless indicatedotherwise by the prefix that indicates the number of carbon members,alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein.

“Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

Unless indicated otherwise by the prefix that indicates the number ofcarbon members, “cycloalkyl” includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.

Unless indicated otherwise by the prefix that indicates the number ofmembers in the cyclic structure, “heterocyclyl”, “heterocyclic” or“heterocycle” is a 3- to 8-member aromatic, saturated, or partiallysaturated single or fused ring system that comprises carbon atomswherein the heteroatoms are selected from N, O, and S. Examples ofheterocyclyls include thiazolyl, furyl, pyranyl, isobenzofuranyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, indolinyl, and morpholinyl. For example, preferredheterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl,pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and morepreferably, piperidyl.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridged, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on. Unlessindicated otherwise, the terms “heteroaryl” or “heteroaromatic” refer tothose heterocycles that are aromatic in nature. Examples illustratingheteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl,thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, pyridyl, and pyrimidinyl.

“Halo” includes fluoro, chloro, bromo, and iodo, and is preferablyfluoro or chloro.

The term “carbonyl” refers to a >C═O moiety, such that when this term ischaracterized as being part of a chain or cyclic structure, the carbonmember in the carbonyl group is taken as being one of the carbon membersof such chain or cyclic structure.

As in standard chemical nomenclature, the group phenyl is hereinreferred to as “phenyl” or as “Ph”.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum mass of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

It is understood that substitutions and combinations of substitutionsrecited herein, whether stated explicitly or not, refer to substitutionsthat are consistent with the valency of the member being substituted.Terms such as “valence allowed site,” “valence allowed member,” andmorphological variations thereof are used in this sense. For example,“valence allowed” when applied to a carbon member refers to thetetravalency of C; it refers to the trivalency of N when applied to anitrogen member; and it refers to the bonding of a nitrogen member thatis conventionally characterized with a positive electric charge or thatis in a quaternary form. The present invention also encompassescompounds as described herein and equivalents thereof with at least onevalence allowed nitrogen member, including but not limited to aquaternary nitrogen member and a nitrogen oxide, each of which may beprepared according to known methods (see J. March, Advanced OrganicChemistry, 4th ed., 1991, pp. 411-412, 1200-1201; R. C. Larock,Comprehensive Organic Transformations, 1989, pp. 397-400, 421-425; andreferences cited therein).

Particular preferred compounds of the invention comprise a compound offormula (I), or an enantiomer, diastereomer, racemate, tautomer,hydrate, solvate thereof, or a pharmaceutically acceptable salt, amideor ester thereof, wherein B¹, B⁵, B⁸, R^(a), R², R³, R⁶, R⁷, m, n, X, Y,and A have any of the meanings defined hereinabove and equivalentsthereof, or at least one of the following assignments and equivalentsthereof. Such assignments may be used where appropriate with any of thedefinitions, claims or embodiments defined herein:

-   each of B¹, B⁵, and B⁸ is CH;-   B¹ is N, B⁵ is N, and B⁸ is CH;-   B¹ is N, B⁵ is CH, and B⁸ is CH;-   B¹ is CH, B⁵ is N, and B⁸ is CH;-   R^(a), R², R³, R⁶, and R⁷ are each independently selected from —H,    —C₁₋₃alkyl, —OC₁₋₃alkyl, halo, or —CF₃;-   R^(a) is —H or —CF₃;-   R² is —H, —CH₃, or —CF₃;-   R⁶ is —H, —OC₁₋₃alkyl, or halo;-   R⁶ is —OC₁₋₃alkyl;-   R⁶ is —H, —OCH₃, or —F;-   R⁶ is —OCH₃;-   R⁷ is —H or —Cl;-   N2-attached regioisomer;-   m=n=1;-   n is 2 and m is 1;-   X is N;-   X is CH;-   X is CH, and Y is —N(benzyl)CH₂—, —N(CH₂CO₂tBu)CH₂—,    —N(CH₂CO₂H)CH₂—, —NHCH₂—, —NH(CH₂)₃—, —NHCH₂CHCH—, —NHCH₂C(Me)CH—,    —NHC(O)—, —NHC(O)CHCH—, —NHCH₂C(O)NH—, —NHCH₂C(O)NHCH₂—,    —NHCH₂C(O)—, —NHC(O)C(O)—, —NH(CH₂)₂O—, or    —NHC(O)C(R^(g1))(R^(g2))—;-   X is CH, and Z is one of C₁₋₃alkylene, C₁₋₃alkenylene,    —C(O)C₂alkenyl-, —(CH₂)₀₋₁C(O)—, —CH₂C(O)N(R^(f))(CH₂)₀₋₁—,    —(CH₂)₂₋₃O—, and —C(O)C(R^(g1)R^(g2))—;-   X is CH, R^(e) is H and Z is C═O;-   R⁶ is —OC₁₋₃alkyl, X is CH, B⁸ is CH, B¹ is N and B⁵ is CH, m=n=1,    N2-attached regioisomer, and A is an aryl or heteroaryl ring    selected from the group consisting of a), b) and c) as defined for    compound of formula (I);-   R⁶ is —OC₁₋₃alkyl, X is CH, B⁸ is CH, B¹ is N and B⁵ is N, m=n=1,    N2-attached regioisomer, and A is an aryl or heteroaryl ring    selected from the group consisting of a), b) and c) as defined for    compound of formula (I);-   A is phenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl,    3,4-dichlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,    3,5-difluorophenyl, 2-nitrophenyl, 5-fluoro-2-trifluoromethylphenyl,    4-dimethylaminophenyl, 4-diethylaminophenyl, 4-piperidin-1-ylphenyl,    4-pyrrolidin-1-ylphenyl, 2-fluoro-4,5-dimethoxyphenyl,    2-chloro-5-nitrophenyl, 2-fluoro-3-cyano-4-dimethylaminophenyl,    pyridin-3-yl, 2-chloro-pyridin-3-yl, or pyridin-2-yl;-   A is 4-methyl-3-nitrophenyl, 2-fluoro-4-nitrophenyl,    2,4-difluorophenyl, 3-trifluoromethylphenyl,    5-acetylamino-2-bromophenyl, or 2,4-dichloro-5-fluorophenyl;-   A is 2,3-dihydro-benzo[1,4]dioxin-6-yl,    7-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl,    3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, benzo[1,3]dioxol-5-yl,    2,2-difluoro-benzo[1,3]dioxol-5-yl,    3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl,    3-oxo-4H-benzo[1,4]oxazin-6-yl,    4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, or    4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl;-   A is 8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,    7-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl,    6-chloro-benzo[1,3]dioxol-5-yl,    7-fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    5,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    3-oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,    2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    7-ethoxycarbonyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, or    7-carboxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl; and-   A is 4,6-difluoro-1H-indol-2-yl, 1H-benzimidazol-2-yl,    1H-indol-2-yl, benzo[b]thiophen-2-yl,    4-fluoro-benzo[b]thiophen-2-yl, benzofuran-2-yl, thiophen-2-yl,    quinoxalin-2-yl, 5-bromo-thiophen-2-yl, 5-acetyl-thiophen-2-yl,    5,6-difluoro-1H-indol-2-yl, 5-methyl-1H-indol-2-yl,    5-bromo-1H-indol-2-yl, or 5-chloro-1H-indol-2-yl.

Compounds of formula (I) comprise compounds that satisfy any one of thecombinations of definitions given herein and equivalents thereof.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical isomers, includingdiastereoisomers and racemic mixtures, atropisomers, and geometricisomers that possess the activity that characterizes the compounds ofthis invention. In addition, certain compounds referred to herein canexist in solvated as well as unsolvated forms. It is understood thatthis invention encompasses all such solvated and unsolvated forms thatpossess the activity that characterizes the compounds of this invention.Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. An example of such compounds is an isotopically labeledcompound, such as an ¹⁸F isotopically labeled compound that may be usedas a probe in detection and/or imaging techniques, such as positronemission tomography (PET) and single-photon emission computed tomography(SPECT). Another example of such compounds is an isotopically labeledcompound, such as a deuterium and/or tritium labeled compound that maybe used in reaction kinetic studies.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but that converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, H. Bundgaard, ed., Elsevier, 1985.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent, such as water; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

Embodiments of this invention are made according to the syntheticmethods outlined in Schemes A-C, have demonstrated antibacterialactivity, and are selected from:

Ex. Compound Name 1 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 27-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 33,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 43-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 57-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;6 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;7 4,6-Difluoro-1H-indole-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 81H-Benzoimidazole-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 92-(1H-Indol-2-yl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-2-oxo-acetamide; 10N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-phenyl-acrylamide; 113-(3,5-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 123-(3-Chloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 133-(4-Fluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 14N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-(3-nitro-phenyl)-acrylamide; 156-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carbonyl]-4H-benzo[1,4]thiazin-3-one; 162,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-quinolin-4- yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;17 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy- quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;18 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;19 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide;20 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;21 1H-Indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro- 2H-indazol-5-yl]-amide;22 4,6-Difluoro-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)- 4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;23 Benzo[b]thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7- tetrahydro-2H-indazol-5-yl]-amide;24 4-Fluoro-benzo[b]thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)- 4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;25 Benzofuran-2-carboxylic acid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 262-(1H-Indol-2-yl)-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-2-oxo-acetamide; 273-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-amide; 287-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-amide;29 N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-phenyl-acrylamide; 30N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-thiophen-2-yl-acrylamide; 313-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-quinolin-8-yl- 4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide; 327-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (2-quinolin-8-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide; 337-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide; 343-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide; 356-Dimethylamino-2-fluoro-3-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-benzonitrile; 36(3,4-Dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 37Benzo[1,3]dioxol-5-ylmethyl-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 38(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 39(4-Dimethylamino-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 407-Fluoro-6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one; 416-{[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one; 42(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 43(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 446-{[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one; 45[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-propyl)-amine; 46[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-allyl)-amine; 47[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-pyridin-3-yl-allyl)-amine; 48[3-(3,4-Dichloro-phenyl)-propyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 49[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-p-tolyl-propyl)-amine; 50(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 51(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 526-{[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one; 537-Fluoro-6-{[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one; 546-{[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one; 55[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-allyl)-amine; 56[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-methyl-3-phenyl-allyl)-amine; 57[3-(4-Fluoro-phenyl)-allyl]-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 58N-(3,5-Difluoro-phenyl)-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide; 592-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-phenyl-acetamide; 602-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-p-tolyl-acetamide; 61N-(3,5-Difluoro-phenyl)-2-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide; 62N-(3,4-Dichloro-phenyl)-2-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide 636-{2-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetyl}-4H-benzo[1,4]oxazin-3-one; 646-{2-[2-(6-Methoxy-quinolin-4-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]acetyl}-4H-benzo[1,4]oxazin-3-one; 65[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-amine; 666-({Benzyl-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]amino}-methyl)-4H-benzo[1,4]thiazin-3-one; 67[[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-acetic acidtert-butyl ester; 68[[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-acetic acid;69 4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;70 Quinoxaline-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 71 1H-Benzoimidazole-2-carboxylicacid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 72 5-Bromo-thiophene-2-carboxylicacid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 73 5-Acetyl-thiophene-2-carboxylicacid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 745,6-Difluoro-1H-indole-2-carboxylic acid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 755-Methyl-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7- tetrahydro-2H-indazol-5-yl]-amide;76 5-Bromo-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7- tetrahydro-2H-indazol-5-yl]-amide;77 5-Chloro-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7- tetrahydro-2H-indazol-5-yl]-amide;782-Chloro-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-nicotinamide; 794-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 801-(4-Chloro-phenyl)-cyclopentanecarboxylic acid[2-(6-methoxy-quinolin-4- yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;81 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(7-chloro- quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;82 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-fluoro-2-methyl-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 832-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-acetamide; 84N-Benzy1-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide; 85(4-Diethylamino-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 86[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(4-piperidin-1-yl-benzyl)-amine; 87[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(4-pyrrolidin-1-yl-benzyl)-amine; 88(2-Fluoro-4,5-dimethoxy-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 89[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-[3-(2-nitro-phenyl)-allyl]-amine; 903-(4-Chloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 91[3-(5-Fluoro-2-trifluoromethyl-phenyl)-allyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 923-(3,4-Dichloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 933-(3,4-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 943-(2-Chloro-5-nitro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 95N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-pyridin-2-yl-acrylamide; 963-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(2,8-bis-trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide;97 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(2-trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide;98 7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide;993-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid [1-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide; 100(8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 101(8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 1023,4-Dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 103(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 104(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 105N-((6-chlorobenzo[d][1,3]dioxol-5-yl)methyl)-2-(6-methoxy-1,5-naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine; 106(7-Fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-quinolin-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 107(7-Fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 1085,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2- (6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;109 5,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 110N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-methyl-3-nitro-benzamide; 111N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-methyl-3-nitro-benzamide; 1123-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 1137-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;114 7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;1153-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 116 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-methoxy- quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;117 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 1182-Fluoro-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-nitro-benzamide; 1194-Methoxy-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-nitro-benzamide; 1203-(2,4-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide; 121[2-(3,5-Difluoro-phenoxy)-ethyl]-{2[1-(6-methoxy-quinolin-4-yl)-1H-pyrazol-4-yl]-1-methyl-ethyl}-amine; 1222-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide; 123N-(3-Chloro-phenyl)-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide; 1245-Acetylamino-2-bromo-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-benzamide; 1252,4-Dichloro-5-fluoro-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-benzamide; 1266-Dimethylamino-2-fluoro-3-{[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-benzonitrile; 1278-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 1288-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 1292,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2- (6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;130 7-Methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 131 7-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid [2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide; 1327-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6- methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide;133 7-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide;134[2-(3,5-Difluoro-phenoxy)-ethyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine; 1356-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylic acidethyl ester; 1366-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylic acid,potassium salt; 1376-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylic acidethyl ester; 1386-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylic acidand 1396-{[1-(2-Trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one.

Compounds according to the present invention may be made according toprocesses within the skill of the art and/or according to processes ofthis invention, such as those described in the schemes and examples thatfollow and by matrix or combinatorial methods. To obtain the variouscompounds herein, starting materials may be employed that carry theultimately desired substituents though the reaction scheme with orwithout protection as appropriate. Starting materials may be obtainedfrom commercial sources or synthesized by methods known to one skilledin the art. Alternatively, it may be necessary to employ, in the placeof the ultimately desired substituent, a suitable group, which may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Those of ordinary skill in the art will be able tomodify and adapt the guidance provided herein to make compoundsaccording to the present invention.

Embodiments of processes illustrated herein include, when chemicallymeaningful, one or more steps such as hydrolysis, halogenation,protection, and deprotection. These steps can be implemented in light ofthe teachings provided herein and the ordinary skill in the art.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of this invention may be modified by usingprotecting groups; such compounds, precursors, or prodrugs are alsowithin the scope of the invention. This modification may be achieved bymeans of conventional protecting groups, such as those described in“Protective Groups in Organic Chemistry”, J. F. W. McOmie, ed., PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 3^(rd) ed., John Wiley & Sons, 1999. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Table of Acronyms Term Acronym Tetrahydrofuran THF N,N-DimethylformamideDMF N,N-Dimethylacetamide DMA Dimethyl sulfoxide DMSOtert-Butylcarbamoyl Boc Bovine serum albumin BSA High-pressure liquidchromatography HPLC Thin layer chromatography TLCN,N-diisopropylethylamine DIEA Triethylamine TEA1,8-Diazabicyclo[5.4.0]undec-7-ene DBU 1-(3-Dimethylaminopropyl)-3- EDCethylcarbodiimide hydrochloride 1-Hydroxybenzotriazole HOBTMethicillin-resistant Staphylococcus aureus MRSA

Referring to Scheme A, bicyclic alcohols A1 may be commerciallyavailable, or may be prepared as described in the Examples below.Conversion of alcohols A1 to the corresponding bromides (not shown) maybe accomplished using various brominating reagents, such as PBr₃, PBr₅,or HBr, neat or in a suitable solvent such as DMF. Preferably, PBr₃ inDMF is used. Hyrazines A2 may be prepared from the bromides by treatmentwith hydrazine, in a polar solvent such as 1-methyl-2-pyrrolidinone,EtOH, or 2-methoxyethanol, at temperatures between room temperature andthe boiling point of the solvent. Preferred solvents include1-methyl-2-pyrrolidinone and EtOH. Elevated temperatures may serve toincrease the rate of the desired reaction and reduce the incidence ofside reactions.

Hydrazines A2 may then be condensed with ketones A3, where G is >NProor >C(H)—NHPro, to form compounds A4. The variable “Pro” refers to asuitable nitrogen protecting group, including tert-butylcarbamoyl (Boc),benzyl, or substituted benzyl. The condensation reaction may beperformed in the presence of an acid such as p-toluenesulfonic acid,acetic acid, or HCl, in a suitable solvent such as THF, EtOH, or CH₃OH.Alternatively, the reaction can take place without acid, in a proticsolvent such as EtOH or CH₃OH. Preferably, reactions are performed usingp-toluenesulfonic acid in THF.

The protecting group in compounds of formula A4 may be removed usingmethods known to one skilled in the art to form amines of formula A5.For example, where a Boc group is employed, it may be removed using HCl,TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH, dioxane, orCH₂Cl₂. Preferably, a Boc group is removed with HCl in dioxane. Where abenzyl group is used, it may be removed by catalytic hydrogenationconditions including a catalyst such as Pd black or Pd/C, a hydrogensource such as cyclohexadiene, ammonium formate, or gaseous H₂, and in asolvent such as CH₃OH, EtOH, or EtOAc. Alternatively, the benzyl groupmay be removed using a Lewis acid such as AlCl₃, in a solvent such asbenzene. Preferably, hydrogenation is performed using Pd/C and ammoniumformate in a solvent such as EtOH.

Referring to Scheme B, the reactions are shown starting with compoundsof formula A5 where X is CH and R is NH₂, but it is understood that theymay also be performed on compounds of formula A5 where X is N and R is Hto form compounds of formula (I).

Amines of formula A5 may be converted to amides of formula B2 byreaction with acyl derivatives of formula B1 where LG is OH throughstandard amide coupling methods such as HOBT/EDC, in a solvent such asDMF. Alternatively, acylation may take place through reaction with acompound of formula B1 where LG is chloride, in the presence of asuitable tertiary amine base such as Et₃N, in a solvent such as CH₂Cl₂.The carbonyl group in amides A5 may be reduced to the methylene using anappropriate reducing agent such as BH₃ to form amines B3. Alternatively,amines B3 may be prepared directly from amines A5 through reductiveamination with an aldehyde of formula B4. Reductive amination may beperformed with or without the addition of an activating agent such asmolecular sieves, AcOH, or Ti(OiPr)₄, followed by a reducing agent suchas NaBH₃CN, NaB(OAc)₃H, or NaBH₄, in a solvent such as CH₃OH, DMF,dichloroethane, or THF. Preferred conditions include NaB(OAc)₃H, in thepresence of catalytic acetic acid, in a solvent such as dichloroethane;NaBH₄ in a solvent such as CH₃OH; or NaBH₄ and Ti(OiPr)₄ in a solventsuch as CH₃OH.

Amines A5 may also be alkylated with suitable halides B5 (where HAL isCl, Br, OTs, or I) to form amines B6 where Z is C₁₋₃alkylene,C₃alkenylene, or CH₂C(O) where the CH₂ in this group CH₂C(O) is attachedto the HAL group. Alkylation may be accomplished in the presence of abase such as K₂CO₃, Et₃N, NaHCO₃, DIEA, with or without catalytic NaI,in a solvent such as DMF, acetone, CH₃CN, EtOH, or THF, at temperaturesbetween room temperature and the boiling temperature of the solventused. Preferably, alkylation employs Et₃N, or K₂CO₃ with catalytic NaI,in a solvent such as DMF, at about 50° C.

Compounds of formulae B2, B3, and B6 represent compounds of formula (I)where R^(e) is —H.

Referring to Scheme C, compounds of formula B2, B3, or B6 may bealkylated, reductively aminated, or acylated using methods known to oneskilled in the art to install the R^(e) substituent and form compoundsof formula C1. Compounds of formula C1 represent compounds of formula(I) where R^(e) is not —H.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as resolution, for exampleby formation of diastereomeric salts, kinetic resolution includingvariants thereof, such as dynamic resolution, preferentialcrystallization, biotransformation, enzymatic transformation, andpreparative chromatography. The compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericamines, esters, or amides, followed by chromatographic separation andremoval of the chiral auxiliary. Alternatively, the compounds may beseparated using a chiral HPLC column. Regioisomeric mixtures may also beseparated into their constituent regioisomers by conventionaltechniques. Similarly, compounds of the present invention may exist inatropisomeric forms, and such forms may be separated using conventionalmethods.

For therapeutic use, salts of the compounds of the present invention arethose that are pharmaceutically acceptable. However, salts of acids andbases that are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound. All salts, whether pharmaceutically acceptable ornot are included within the ambit of the present invention.

Pharmaceutically acceptable salts, esters, and amides of compoundsaccording to the present invention refer to those salt, ester, and amideforms of the compounds of the present invention which would be apparentto the pharmaceutical chemist, i.e., those which are non-toxic and whichwould favorably affect the pharmacokinetic properties of said compoundsof the present invention. Those compounds having favorablepharmacokinetic properties would be apparent to the pharmaceuticalchemist, i.e., those which are non-toxic and which possess suchpharmacokinetic properties to provide sufficient palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof raw materials, ease of crystallization, yield, stability,hygroscopicity and flowability of the resulting bulk drug.

Examples of acids that may be used in the preparation ofpharmaceutically acceptable salts include the following: acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid,(−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonicacid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid,phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid,4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Compounds of the present invention containing acidic protons may beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts; the alkali and earth alkaline metal salts (e.g. lithium, sodium,potassium, magnesium, calcium salts, which may be prepared by treatmentwith, for example, magnesium hydroxide, calcium hydroxide, potassiumhydroxide, zinc hydroxide, or sodium hydroxide); and amine salts madewith organic bases (e.g. primary, secondary and tertiary aliphatic andaromatic amines such as L-arginine, benethamine, benzathine, choline,deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glutamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g.,S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19, which is incorporated herein by reference.

“Salt” also comprises the hydrates and solvent addition forms thatcompounds of the present invention are able to form. Examples of suchforms are hydrates, alcoholates, and generally solvates.

Examples of suitable esters include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl,substituted phenyl, and phenylC₁₋₆alkyl-esters. Preferred esters includemethyl esters. Furthermore, examples of suitable esters include suchesters where one or more carboxyl substituents is replaced withp-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxycarbonyl,9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl,tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl,benzoylmethoxycarbonyl, p-nitrobenzyloxy-carbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl,2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, ortetrahydropyran-2-yloxycarbonyl.

Whether referred to herein explicitly or not, each of the terms“pharmaceutically acceptable salts,” “pharmaceutically acceptableesters,” and “pharmaceutically acceptable amides” include those salts,esters and amides, respectively that do not change the intrinsicproperties of the active ingredient. See, for example, Remington, TheScience and Practice of Pharmacy, 704 (20^(th) ed., 2000).

“Subject” or “patient” refers to eukaryotic organisms and it includesmammals such as human beings and animals (e.g., dogs, cats, horses,rats, rabbits, mice, non-human primates) in need of observation,experiment, treatment or prevention in connection with the relevantdisease or condition. Preferably, the patient or subject is a humanbeing.

“Composition” includes a product comprising the specified ingredients inthe specified amounts, including in the effective amounts, as well asany product that results directly or indirectly from combinations of thespecified ingredients in the specified amounts.

Administration of at least one compound of formula (I) and/or derivativethereof refers to the administration of such compound in a suitableadministration form, whether as such compound itself or as part of asuitable pharmaceutical composition.

“Therapeutically effective amount” or “effective amount” andgrammatically related terms mean that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein an in vitro system, a tissue system, an animal or human being, thatis being sought by a researcher, veterinarian, medical doctor, or otherclinician, where the medicinal response includes, but is not limited to,alleviation of the symptoms of the disease or disorder being treated.Analogously, terms such as “inhibitory amount”, “anti-microbial amount”,“anti-infective amount”, “antibacterial amount”, “prophylacticallyeffective amount”, and grammatically related terms refer to the amountof active compound or pharmaceutical agent that elicits the responsebeing referred to, such as inhibition and antibacterial effect, in thesystem being studied, whether an in vitro system, an animal or a humanbeing that is sought by a researcher, veterinarian, medical doctor, orother clinician, where the medicinal response includes, but is notlimited to, alleviation of the symptoms of the disease or disorder beingtreated. The laboratory practice of assays and the criteria forascertaining in light of such assays the effects referred to herein arewell-known and they are part of the standard practice in this field, andtherefore are not provided explicitly herein. Similarly, specificselections of embodiments of this invention according to their effectsdetermined by such assays can be done as a matter of routineexperimentation by using such assays and the teachings provided herein.Effects of embodiments of this invention are manifested against bacteriain a plurality of eukaryotic organisms. Accordingly, the specific hostin which the antibacterial effect is manifested is not a limitation ofthe present invention. In addition to medicine, fields of use ofembodiments of this invention include veterinarian applicationsencompassing areas such as aquaculture.

Embodiments of this invention include methods for inhibiting bacterialactivity. Inhibition effects include, but are not limited to, inhibitionof at least one of DNA gyrase, topoisomerase IV, MRSA,ciprofloxacin-resistant (CipR) MRSA, and combinations thereof.

As used herein, “treating” a disorder, and grammatically related terms,mean eliminating or otherwise ameliorating the cause and/or effectsthereof. Terms such as to “inhibit”, and grammatically related terms,the onset of a disorder or event, and to “prevent” a disorder orcondition, and grammatically related terms, mean preventing, delaying orreducing the likelihood of such onset.

The terms “unit dose” and their grammatical equivalent forms are usedherein to refer to physically discrete units suitable as unitary dosagesfor human patients and other animals, each unit containing apredetermined effective, pharmacologic amount of the active ingredientcalculated to produce the desired pharmacological effect. Thespecifications for the novel unit dosage forms of this invention aredetermined by, and are directly dependent on, the characteristics of theactive ingredient, and on the limitations inherent in the art ofcompounding such an active ingredient for therapeutic use in humans andother animals.

Compounds of the present invention may be used in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersinvolving bacterial activity. In particular, compounds of the presentinvention may be used in pharmaceutical compositions to treat bacterialinfection.

The present invention features pharmaceutical compositions containingsuch compounds and methods of using such compositions in the treatmentor prevention of conditions that are mediated by bacterial activity.Accordingly, the present invention also contemplates a pharmaceuticalcomposition that comprises at least one compound according to thisinvention, preferably in a pharmaceutically acceptable carrier. The atleast one compound according to this invention is present in suchcomposition in an amount sufficient to inhibit bacterial activity. Moreparticularly, the at least one compound according to this invention ispresent in such composition in an anti-bacterial amount.

Accordingly, a pharmaceutical composition that comprises ananti-bacterial amount of at least one compound according to the presentinvention in a pharmaceutically acceptable carrier is also contemplatedherein. The composition comprises a unit dosage of the at least onecompound according to this invention. In preferred practice, the atleast one compound according to the present invention that is comprisedin the pharmaceutical composition is capable of inhibiting bacterialactivity in the amount at which that compound is present in thepharmaceutical composition, when that pharmaceutical composition isintroduced as a unit dose into an appropriate patient or subject.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques. Examples ofsuitable unit dosage forms are tablets, capsules, pills, powder packets,granules, wafers, and the like, segregated multiples of any unit dosageform, as well as liquid solutions, and suspensions. Oral dosage formsmay be elixirs, syrups, capsules, tablets, and the like. Examples ofsolid carriers include those materials usually employed in themanufacture of pills or tablets, such as lactose, starch, glucose,methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, andthe like, thickeners such as tragacanth and methylcellulose USP, finelydivided SiO₂, polyvinylpyrrolidone, magnesium stearate, and the like.Typical liquid oral excipients include ethanol, glycerol, water, and thelike. All excipients may be mixed as needed with inert diluents (forexample, sodium and calcium carbonates, sodium and calcium phosphates,and lactose), disintegrants (for example, cornstarch and alginic acid),diluents, granulating agents, lubricants (for example, magnesiumstearate, stearic acid, and talc), binders (for example, starch andgelatin), thickeners (for example, paraffin, waxes, and petrolatum),flavoring agents, coloring agents, preservatives, and the like byconventional techniques known to those of ordinary skill in the art ofpreparing dosage forms. Coatings can be present and include, forexample, glyceryl monostearate and/or glyceryl distearate. Capsules fororal use include hard gelatin capsules in which the active ingredient ismixed with a solid diluent, and soft gelatin capsules, in which theactive ingredient is mixed with water or oil, such as peanut oil, liquidparaffin, or olive oil.

Parenteral dosage forms may be prepared using water or another sterilecarrier. For intramuscular, intraperitoneal, subcutaneous, andintravenous use, the compounds of the invention will generally beprovided in sterile aqueous solutions or suspensions, buffered to anappropriate pH and isotonicity. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Aqueous suspensions mayinclude suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone, and gum tragacanth, and a wettingagent, such as lecithin. Suitable preservatives for aqueous suspensionsinclude ethyl and n-propyl p-hydroxybenzoate. Parenteral formulationsinclude pharmaceutically acceptable aqueous or nonaqueous solutions,dispersion, suspensions, emulsions, and sterile powders for thepreparation thereof. Examples of carriers include water, ethanol,polyols (propylene glycol, polyethylene glycol), vegetable oils, andinjectable organic esters such as ethyl oleate. Fluidity can bemaintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbents, (h) lubricants, (i) buffering agents, and(j) propellants.

To aid solubility, suitable ingredients, such as cyclodextrins, may beincluded in the compositions. Appropriate cyclodextrins (CD) are α-, β-,γ-cyclodextrins or ethers and mixed ethers thereof wherein one or moreof the hydroxy groups of the anhydroglucose units of the cyclodextrinare substituted with C₁₋₆alkyl, particularly methyl, ethyl or isopropyl,for example randomly methylated β-CD; hydroxyC₁₋₆alkyl, particularlyhydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC₁₋₆alkyl,particularly carboxymethyl or carboxy-ethyl; C₁₋₆alkylcarbonyl,particularly acetyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD). The term mixed ether denotes cyclodextrin derivativeswherein at least two cyclodextrin hydroxy groups are etherified withdifferent groups such as, for example, hydroxy-propyl and hydroxyethyl.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

Physiologically acceptable carriers are well known in the art. Examplesof liquid carriers are solutions in which compounds according to thepresent invention form solutions, emulsions, and dispersions. Compatibleantioxidants, such as methylparaben and propylparaben, can be present insolid and liquid compositions, as can sweeteners.

Pharmaceutical compositions according to the present invention mayinclude suitable emulsifiers typically used in emulsion compositions.Such emulsifiers are described in standard publications such as H. P.Fiedler, 1989, Lexikon der Hilfsstoffe für Pharmazie, Kosmetic andagrenzende Gebiete, Cantor ed., Aulendorf, Germany, and in Handbook ofPharmaceutical Excipients, 1986, American Pharmaceutical Association,Washington, D.C., and the Pharmaceutical Society of Great Britain,London, UK, which are incorporated herein by reference. Examples ofemulsifiers are given in U.S. Pat. No. 6,352,998, cols. 4-5. Gellingagents may also be added to compositions according to this invention.Polyacrylic acid derivatives, such as carbomers, are examples of gellingagents, and more particularly, various types of carbopol, which aretypically used in amounts from about 0.2% to about 2%. Suspensions maybe prepared as a cream, an ointment, including a water-free ointment, awater-in-oil emulsion, an oil-in-water emulsion, an emulsion gel, or agel.

It is anticipated that the compounds of the invention can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, rectal, and topicaladministration, and inhalation. For oral administration, the compoundsof the invention will generally be provided in the form of tablets,capsules, or as a solution or suspension. Other methods ofadministration include controlled release formulations, such assubcutaneous implants and dermal patches.

Compounds according to the present invention and mixtures thereofprovide embodiments of active substance in pharmaceutical compositionsthat can be made with excipients and ingredients and with ordinary skillin the art.

Lists of excipients and ingredients for pharmaceutical compositions areavailable in standard references. For example, a standard text such asThe Science and Practice of Pharmacy, A. R. Gennaro, ed., provides 20chapters in part 5, pp. 669-1050, on pharmaceutical manufacturing,including lists of ingredients to manufacture pharmaceuticalcompositions such as solutions (including aromatic waters, aqueousacids, douches, enemas, gargles, mouthwashes, juices, nasal solutions,otic solutions, irrigation solutions, syrups, honeys, mucilages,jellies, collodions, elixirs, glycerins, inhalants, liniments,oleopreparations, spirits, and drops), emulsions (including multipleemulsions and microemulsions), suspensions, (including gels, lotions,tablet-formulated suspensions, magmas and milks, mixtures, and officialsuspensions), extracts, parenteral preparations, intravenouspreparations, ophthalmic preparations, topical preparations, oral soliddosage forms, coatings, controlled-release drug delivery systems,aerosols, packaging materials, antioxidants, preservatives, coloringagents, flavoring agents, diluting agents, vehicles, emulsifying agents,suspending agents, ointment bases, pharmaceutical solvents, andmiscellaneous pharmaceutical necessities, including the techniques anddevices for manufacturing such preparations.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition, type of symptoms needing treatment, the routeof administration, the weight, age, and general condition of thepatient, and the administration of other medicaments.

In general, it is anticipated that the daily dose (whether administeredas a single dose or as divided doses) will be in the range from about0.01 mg to about 1000 mg per day, more usually from about 1 mg to about500 mg per day, and most usually form about 10 mg to about 200 mg perday. Expressed as dosage per unit body weight, a typical dose will beexpected to be between about 0.0001 mg/kg and about 15 mg/kg, especiallybetween about 0.01 mg/kg and about 7 mg/kg, and most especially betweenabout 0.15 mg/kg and 2.5 mg/kg.

Anticipated oral dose ranges include from about 0.01 to 500 mg/kg,daily, more preferably from about 0.05 to about 100 mg/kg, taken in 1-4separate doses. Some compounds of the invention may be orally dosed inthe range of about 0.05 to about 50 mg/kg daily, while others may bedosed at 0.05 to about 20 mg/kg daily. Infusion doses can range fromabout 1.0 to about 1.0×10⁴ μg/(kg min) of inhibitor, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days. For topical administration, compounds of the presentinvention may be mixed with a pharmaceutical carrier at a concentrationfrom about 0.1 to about 10% of drug to vehicle. Capsules, tablets orother formulations (such as liquids and film-coated tablets) may be ofbetween 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg,and 100 mg and can be administered according to the disclosed methods.Daily dosages are envisaged to be, for example, between 10 mg and 5000mg for an adult human being of normal weight.

A method for treating a bacterial condition or infection in a patientexhibiting or susceptible to a bacterial condition or infection is alsocontemplated. The methods comprise administering to that patient aneffective amount of a pharmaceutical composition that includes a unitdose of an active ingredient that is at least one of the compoundsaccording to this invention dispersed in a pharmaceutically acceptablecarrier.

EXAMPLES

In order to illustrate the invention, the following examples areprovided. These examples do not limit the invention. They are meant toillustrate embodiments of the invention. Those skilled in the art mayfind additional embodiments in light of the teachings and examplesprovided herein, additional embodiments that are deemed to be within thescope of this invention.

General Experimental Details:

NMR spectra were obtained on a Bruker model DPX400 (400 MHz), DPX500(500 MHz), or DPX600 (600 MHz) spectrometer. The format of the ¹H NMRdata below is: chemical shift in ppm down field of the tetramethylsilanereference (multiplicity, coupling constant J in Hz, integration).

Mass spectra were obtained on a Agilent series 1100 MSD usingelectropsray ionization (ESI) in either positive or negative mode asindicated.

Analytical HPLC retention times are reported in minutes, using thefollowing methods and conditions: Instrument: Agilent HP-1100; Solvent:Acetonitrile/H₂O (20 mM NH₄OH); Temperature: 30° C.; Wavelength: Dualdetection at 220 nm and 254 nm; Method: Xterra RP 18 column (3.5 μm,4.6×100 mm) at 1 mL/min with a 10-min linear gradient ramp from 1% H₂Oto 99% H₂O.

Preparative HPLC was performed under acidic or basic conditions: Acidicconditions: Instrument: Gilson; Solvent: Acetonitrile/H₂O (0.1% TFA);Temperature: 30° C.; Wavelength: Dual detection at 220 nm and 254 nm;Method: Xterra RP 18 column (5 μm, 30×75 mm) at 20 mL/min with agradient ramp from 1% H₂O to 99% H₂O.

Basic conditions: Instrument, Temperature, and Wavelength as above;Solvent: Acetonitrile/H₂O (20 mM NH₄OH); Method: Phenomenex Synergi Max(21.2×150 mm) at 20 mL/min with a gradient ramp from 1% H₂O to 99% H₂O.

Flash column chromatography was accomplished using the ISCO Foxy 200system and one of the following commercially available, pre-packedcolumns: Biotage 40L (SiO₂; 120 g), Biotage 65M (SiO₂; 300 g) or ISCORedisep (SiO₂; 4, 12, 40, 120, or 330 g).

Supercritical fluid chromatography (SFC): Instrument: Thar TechnologiesSFC-50; Solvent: 15% CH₃OH (0.02% Et₃N)/CO₂; Temperature: 30° C.;Pressure: 100 bar; Method: YMC-pack, DIOL-120 NP column (s-5 μm, 12 nm,150×20 mm) at 38 mL/min.

Where solutions are said to be “concentrated,” they are generallyconcentrated under reduced pressure using a rotary evaporator.

Example A

2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine

A.5-[(6-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione.To a solution of 5-amino-2-methoxypyridine (37.2 g, 0.300 mol) in EtOH(225 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid)(51 g, 350 mmol) and triethyl orthoformate (44.5 g, 0.300 mol). Themixture was heated to reflux and stirred for 3 h. The resultingsuspension was cooled to RT, filtered, washed with EtOH (200 mL) anddried in vacuo to provide 75 g (90%) of the title compound as a tansolid. ¹H NMR (500 MHz, DMSO-d₆): 11.26 (d, J=14.6, 1H), 8.45 (d,J=14.6, 1H), 8.38 (d, J=2.9, 1H), 7.97 (dd, J=8.9, 2.9, 1H), 6.88 (d,J=8.9, 1H), 3.86 (s, 3H), 1.67 (s, 6H).

B. 6-Methoxy-[1,5]naphthyridin-4-ol. Dowtherm A (26.5:73.5diphenyl/diphenyl oxide) (140 mL) was added to a three-neck flask fittedwith an air-condenser, thermocouple and a funnel and the solvent washeated to 260° C. To the Dowtherm A was added5-[(6-methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(34.8 g, 125 mmol) over a period of 10 min, keeping the temperatureabove 250° C. The funnel was rinsed with Dowtherm A (20 mL). Thereaction mixture was heated for a further 4 min and then removed fromthe heat source. The resulting suspension was cooled to RT and treatedwith Et₂O (200 mL). The solid was filtered, washed with Et₂O (300 mL),hexanes (500 mL) and dried in vacuo to provide 18.8 g (85%) of the titlecompound as a tan solid. ¹H NMR (500 MHz, DMSO-d₆): 11.88 (br s, 1H),8.13 (br s, 2H), 7.17 (s, 1H), 6.22 (br s, 1H), 3.93 (s, 3H).

C. 8-Bromo-2-methoxy-[1,5]naphthyridine. To a suspension of6-methoxy-[1,5]naphthyridin-4-ol (8.8 g, 0.050 mol) in DMF (167 mL) wasadded PBr₃ (4.7 mL, 0.050 mol) at 45° C. The suspension becamehomogeneous and then a suspension formed over 20 min. The mixture wascooled to RT and the solid was filtered and washed with Et₂O (100 mL).Further solids precipitated from the filtrate and were collected. Water(50 mL) was added to the solid and the suspension was basified with 1 NNaOH (200 mL). The aqueous layer was extracted with CH₂Cl₂ (3×250 mL),washed with brine (150 mL), dried (MgSO₄) and concentrated. Theresulting residue was purified on SiO₂ (0-60% EtOAc/hexanes) to provide8.9 g (75%) of the title compound as a white solid. MS (ESI): exact masscalculated for C₉H₇BrN₂O, 237.97; m/z found, 239.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.57 (d, J=4.7, 1H), 8.27 (d, J=9.0, 1H), 8.05 (d, J=4.7,1H), 7.30 (d, J=9.0, 1H), 4.04 (s, 3H).

D. (6-Methoxy-[1,5]naphthyridin-4-yl)-hydrazine. To a solution of8-bromo-2-methoxy-[1,5]naphthyridine (5.1 g, 21 mmol) in EtOH (64 mL)was added hydrazine (1.3 mL, 42 mmol). This solution was heated to 78°C. and stirred for 6 days, by which time the solution had becomeheterogeneous. The suspension was cooled to RT and concentrated. Theresulting solid was dissolved in CH₂Cl₂ (100 mL) and washed with 10% aq.NaOH (100 mL). The aqueous phase was back-extracted with CH₂Cl₂ (2×100mL). The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated to afford 3.4 g (83%) of a brown solid. MS (ESI): exactmass calculated for C₉H₁₀N₄O, 190.09; m/z found, 191.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.51 (d, J=5.2, 1H), 8.11 (d, J=9.1, 1H), 7.08 (d,J=9.1, 1H), 6.92 (d, J=5.2, 1H), 4.03 (s, 3H), 3.73 (d, J=2.8, 2H).

E.[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamicacid tert-butyl ester. To a solution of (4-oxo-cyclohexyl)-carbamic acidtert-butyl ester (5.00 g, 23.2 mmol) in THF (116 mL) was addedtert-butoxy bis(dimethylamino)methane (9.6 mL, 46 mmol). The solutionwas heated to 65° C. and stirred for 24 h. The solution was cooled toRT, 10% aq. HCl (100 mL) was added, and the mixture was stirred for 3.5h. The mixture was extracted with CH₂Cl₂ (2×200 mL). The combinedorganic extracts were washed with 10% aq. HCl (150 mL), dried (Na₂SO₄),filtered, and concentrated to afford 5.4 g of a brown oil,(3-hydroxymethylene-4-oxo-cyclohexyl)-carbamic acid tert-butyl ester,which was used without further purification, in the following step andlater examples. To this oil (3.4 g, 14 mmol) was added(6-methoxy-[1,5]naphthyridin-4-yl)-hydrazine (3.23 g, 16.7 mmol),followed by THF (44.4 mL). The solution was stirred at RT for 4 h.p-Toluenesulfonic acid (7.9 g, 42 mmol) was added, and the deep redsolution was stirred at RT for 13 h. The solution was poured intosaturated (satd.) aq. NaHCO₃ (100 mL) and extracted with CH₂Cl₂ (4×150mL). The organic extracts were dried (Na₂SO₄), filtered, andconcentrated to a crude oil, which was purified on SiO₂ (0-100%EtOAc/hexanes) to provide 2.75 g (50%) of a brown oil. MS (ESI): exactmass calculated for C₂₁H₂₅N₅O₃, 395.20; m/z found, 396.5 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.11 (s, 1H), 8.78 (d, J=5.1, 1H), 8.27 (d, J=9.1,1H), 8.16 (d, J=5.1, 1H), 7.19 (d, J=9.1, 1H), 4.67-4.66 (m, 1H), 4.10(s, 3H), 4.07-4.03 (m, 1H), 3.13-3.09 (m, 1H), 2.96-2.92 (m, 2H),2.58-2.54 (m, 1H), 2.15-2.10 (m, 1H), 1.99-1.90 (m, 1H), 1.55 (s, 9H).

F. To a solution of[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamicacid tert-butyl ester (317 mg, 0.800 mmol) in CH₂Cl₂ (3.6 mL) was added4 M HCl in dioxane (3.40 mL, 13.7 mmol), and the solution was stirred atRT for 3.5 h. The solution was concentrated to afford a crude solid,which was dissolved in CH₃OH (10 mL). Anionic exchange resin (550 Å OH,100 mg) was added and the mixture was stirred for 20 min. The mixturewas filtered, and the resin was washed with CH₃OH (30 mL). The filtratewas concentrated to afford 234 mg (99% crude) of the title compound as abrown oil. MS (ESI): exact mass calculated for C₁₆H₁₇N₅O, 295.14; m/zfound, 296.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.08 (s, 1H), 8.76 (d,J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.18 (d, J=9.1,1H), 4.10 (s, 3H), 3.29-3.27 (m, 1H), 3.01-2.96 (m, 2H), 2.87-2.80 (m,1H), 2.48-2.39 (m, 1H), 2.11-2.05 (m, 1H), 1.82-1.64 (m, 3H).

Example B

2-(6-Methoxy-[1,5]naphthyridin-4-yl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene

A. 4-Hydroxymethylene-5-oxo-azepane-1-carboxylic acid tert-butyl ester.To a solution of 4-oxo-azepane-1-carboxylic acid tert-butyl ester (1.0g, 4.7 mmol) in THF (16 mL) was addedtert-butoxybis(dimethylamino)methane (2.0 mL, 9.4 mmol) and the reactionwas heated at 65° C. for 12 h. Upon cooling to RT, the reaction wasdiluted with 1 N HCl (10 mL) and stirred for 3 h at the sametemperature. The reaction was diluted with Et₂O (30 mL). The organiclayer was separated and the aqueous layer was extracted with Et₂O (2×20mL). The combined organic layers were washed with 1 N NaOH (40 mL),brine (20 mL), dried (MgSO₄), filtered, and concentrated to afford 1.1 g(100% crude) of the title compound as a pale yellow oil whichconstituted of an inseparable mixture of isomers. ¹H NMR (500 MHz,CDCl₃): 14.88 (br s, 0.2H), 14.40 (d, J=9.2, 0.8H), 7.81-7.62 (m, 1H),3.90-3.88 (m, 2H), 3.57-3.47 (m, 2H), 2.67-2.65 (m, 2H), 1.80-1.75 (m,2H), 1.46-1.35 (m, 9H).

B.2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylicacid tert-butyl ester. To a solution of4-hydroxymethylene-5-oxo-azepane-1-carboxylic acid tert-butyl ester (500mg, 2.0 mmol) in THF (7 mL) was added(6-methoxy-[1,5]naphthyridin-4-yl)-hydrazine (480 mg, 2.4 mmol). Thereaction was stirred at RT for 4 h. Then p-toluenesulfonic acid (600 mg,6.0 mmol) was added and the reaction was stirred at RT for an additional12 h. The reaction was diluted with CH₂Cl₂ (30 mL) and 1 N NaOH (40 mL).The organic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (2×20 mL). The combined organic layers were washed with 1 N NaOH(50 mL), brine (30 mL), dried (MgSO₄), filtered and concentrated. Theresidue was purified on SiO₂ (60% EtOAc/hexanes) to afford 510 mg (65%)of the title compound as a pale yellow oil. ¹H NMR (7:3 mixture ofisomers; 500 MHz, CDCl₃): 9.25-9.22 (m, 0.7H), 9.14 (s, 0.3H), 8.75 (d,J=5.0, 1H), 8.27-8.12 (m, 2H), 7.19-7.15 (m, 1H), 4.43-4.39 (m, 1H),4.12 (s, 3H), 3.71-3.57 (m, 2H), 3.05-2.99 (m, 2H), 2.81-2.79 (m, 0.7H),1.90-1.87 (m, 1.3H), 1.69-1.65 (m, 1H), 1.50 (s, 3H), 1.40 (s, 6H).

C. This compound was prepared according to the method described inExample A, Step F. The title compound was a pale yellow foam (mixture ofisomers). MS (ESI): exact mass calculated for C₁₆H₁₇N₅O, 295.14; m/zfound, 296.30 [M+H]⁺.

Example C

2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine

A.5-[(4-Methoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione.This compound was prepared according to the methods described in ExampleA, Step A. ¹H NMR (400 MHz, CDCl₃): 11.26 (d, J=14.3, 1H), 8.57 (d,J=14.3, 1H), 7.24-7.20 (m, 2H), 7.00-6.96 (m, 2H), 3.87 (s, 3H), 1.78(s, 6H).

B. 4-Bromo-6-methoxy-quinoline. The title compound was prepared asdescribed in Example A, Steps B and C to give a crude solid. In Step C,the reaction mixture was heated to 80° C. instead of 45° C.Recrystallization gave 2.02 g (36%) of a white solid. ¹H NMR (400 MHz,CDCl₃): 8.53 (d, J=4.7, 1H), 8.00-7.98 (m, 1H), 7.66 (d, J=4.7, 1H),7.41-7.39 (m, 2H), 3.98 (s, 3H).

C. (6-Methoxy-quinolin-4-yl)-hydrazine. To a solution of4-bromo-6-methoxy-quinoline (5.4 g, 28 mmol) in 1-methyl-2-pyrrolidinone(27 mL) was added hydrazine (1.52 mL, 33.6 mmol). The reaction washeated at 150° C. for 12 h. The reaction was then cooled to RT and addeddropwise to an ethereal solution (700 mL) at RT. The white precipitatewas collected by filtration, washed with Et₂O (80 mL), and dried underreduced pressure. The resulting solid was dissolved in CH₂Cl₂ (100 mL)and washed with 1 N NaOH (100 mL). The aqueous layer was back-extractedwith CH₂Cl₂ (2×100 mL). The combined organic layers were washed with 1 NNaOH (50 mL), brine (30 mL), dried (MgSO₄), filtered and concentrated toafford 4.3 g (82% crude) of a brown solid. HPLC: R_(t)=4.22 min. MS(ESI): exact mass calculated for C₁₀H₁₁N₃O, 189.1; m/z found, 190.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.26 (d, J=6.5, 1H), 7.75 (d, J=9.2,1H), 7.52 (d, J=2.5, 1H), 7.46 (dd, J=9.2, 2.6, 1H), 7.19 (d, J=6.5,1H), 3.95 (s, 3H).

D.[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamicacid tert-butyl ester. The reaction was performed according to themethods described in Example A, Step E. The crude residue was purifiedon SiO₂ (20% (2.5% (CH₃OH/EtOAc)/CH₂Cl₂) to afford 510 mg (65%) of thetitle compound as a pale yellow oil. MS (ESI): exact mass calculated forC₂₂H₂₆N₄O₂, 394.20; m/z found, 395.39 [M+H]⁺. ¹H NMR (3:2 mixture ofisomers; 500 MHz, CDCl₃): 8.84 (d, J=4.6, 0.4H), 8.79 (d, J=4.7, 0.6H),8.08-8.06 (m, 1H), 7.64-7.62 (m, 1H), 7.44-7.41 (m, 1H), 7.34 (d, J=4.7,0.6H), 7.30 (d, J=4.6, 0.4H), 7.01 (s, 1H), 4.75-4.65 (m, 1H), 4.13-4.01(m, 1H), 3.91 (s, 2H), 3.83 (s, 1H), 3.82 (t, J=7.0, 1H), 2.84-2.80 (m,1H), 2.70-2.60 (m, 2H), 2.37 (t, J=7.0, 1H), 2.04-1.89 (m, 1H), 1.62 (s,3.6H), 1.48 (s, 5.4H).

E. The target compound was prepared according to the methods describedin Example A, Step F, to obtain a pale yellow foam. MS (ESI): exact masscalculated for C₁₇H₁₈N₄O, 294.15; m/z found, 295.31 [M+H]⁺. ¹H NMR (3:2mixture of isomers; 500 MHz, CDCl₃): 8.82-8.81 (m, 0.4H), 8.76-8.75 (m,0.6H), 8.06-8.05 (m, 1H), 7.68-7.65 (m, 1H), 7.42 (d, J=9.1, 1H), 7.34(d, J=7.3, 1H), 7.30 (d, J=5.7, 0.6H), 7.08-7.07 (m, 0.4H), 3.90 (s,2H), 3.83 (s, 1H), 3.38 (t, J=7.0, 1H), 3.35-3.28 (m, 1H), 3.01-2.81 (m,1H), 2.6 (br s, 1H), 2.48-2.35 (m, 2H), 2.11-1.97 (m, 2H), 1.80-1.70 (m,1H).

Example D

2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-ylamine

A.[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-carbamicacid tert-butyl ester. This compound was prepared according to methodsdescribed for Example A, Step E. MS (ESI): exact mass calculated forC₂₂H₂₆N₄O₃, 394.20; m/z found, 395.8 [M+H]⁺. ¹H NMR (2:1 mixture ofisomers; 500 MHz, CDCl₃): 8.77-8.76 (m, 1H), 8.05-8.03 (m, 1H), 7.86 (brs, 0.5H), 7.64 (br s, 0.5H), 7.62 (br s, 1H), 7.41-7.38 (m, 1H),7.32-7.29 (m, 1H), 4.87 (br s, 1H), 4.72 (br s, 0.5H), 4.12-4.00 (m,1H), 3.88 (s, 3H), 3.20 (dd, J=16.1, 4.9, 0.5H), 2.83-2.76 (m, 2H), 2.67(dd, J=16.0, 8.2, 0.5H), 2.15-2.08 (m, 1H), 2.02-1.95 (m, 1.5H),1.94-1.74 (m, 1.5H), 1.73-1.61 (m, 0.6H), 1.60-1.54 (m, 0.2H), 1.45 (s,9.5H), 1.25-1.21 (m, 0.6H).

B. The target compound was prepared according to the methods describedin Example A, Step F. The crude product was used without furtherpurification.

Example E

6-Methoxy-4-(4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-quinoline

A. 3-Hydroxymethylene-4-oxo-piperidine-1-carboxylic acid benzyl ester.The reaction was performed according to the methods described in ExampleB, Step A, to obtain a pale yellow oil (mixture of isomers) that wasused in the next step without further purification. ¹H NMR (500 MHz,CDCl₃): 8.48 (br s, 0.7H), 7.35-7.25 (m, 5H), 5.15 (s, 1.5H), 5.11 (s,0.5H), 4.34 (s, 1.5H), 4.17 (s, 0.5H), 3.74-3.72 (m, 0.5H), 3.67-3.64(m, 1.5H), 2.49-2.44 (m, 1.5), 1.85-1.83 (m, 0.5H).

B.2-(6-Methoxy-quinolin-4-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid benzyl ester. This reaction was performed according to the methodsdescribed in Example B, Step B. The crude residue was purified on SiO₂(20% (2.5% CH₃OH/EtOAc)/CH₂Cl₂) to afford 700 mg (85%) of the titlecompound as a pale yellow oil. ¹H NMR (3:2 mixture of isomers; 500 MHz,CDCl₃): 8.84-8.82 (m, 0.6H), 8.79-8.77 (m, 0.4H), 8.08-8.06 (m, 1H),7.74-7.62 (m, 2H), 7.42-7.33 (m, 5H), 7.26-7.25 (m, 0.6H), 7.12 (s,0.4H), 5.19 (s, 2H), 4.72 (s, 0.8H), 4.62 (s, 1.2H), 3.88 (s, 2H),3.82-3.78 (m, 3H), 3.36 (td, J=6.9, 3.3, 0.6H), 2.96 (s, 0.4H), 2.67 (s,1H), 2.34 (t, J=7.9, 0.6H).

C. To a solution of2-(6-methoxy-quinolin-4-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid benzyl ester (300 mg, 0.7 mmol) in EtOH (3 mL) was added HCO₂NH₄(70 mg, 1 mmol) and 10% Pd/C (300 mg). The mixture was stirred at RT for16 h. The crude mixture was filtered through diatomaceous earth, washingwith EtOH (10 mL), and the filtrate was concentrated to afford 203 mg(100% crude) of the title compound as a pale yellow foam. MS (ESI):exact mass calculated for C₁₆H₁₆N₄O, 280.13; m/z found, 281.32 [M+H]⁺.¹H NMR (3:2 mixture of isomers; 500 MHz, CDCl₃): 8.80-8.79 (m, 0.6H),8.78-8.76 (m, 0.4H), 8.08-8.05 (m, 1H), 7.73-7.62 (m, 2H), 7.24-7.18 (m,0.6H), 7.11 (s, 0.4H), 5.00 (s, 2H), 4.68 (s, 0.8H), 4.52 (s, 1.2H),3.61-3.58 (m, 3H), 3.01 (td, J=6.9, 3.3, 0.6H), 2.54 (s, 0.4H), 2.38 (s,1H), 2.02 (t, J=7.9, 1H).

Example F

2-Quinolin-8-yl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine

A. (2-Quinolin-8-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-carbamic acidtert-butyl ester. The reaction was performed according to the methodsdescribed in Example A, Step E. The crude residue was purified on SiO₂(40% EtOAc/hexanes) to afford 320 mg (42%) of the title compound as apale yellow oil. ¹H NMR (500 MHz, CDCl₃): 8.96 (dd, J=4.1, 1.7, 1H),8.45 (s, 1H), 8.23 (dd, J=8.3, 1.7, 1H), 8.13 (dd, J=7.5, 1.2, 1H), 7.75(dd, J=8.3, 1.2, 1H), 7.62 (t, J=7.5, 1H), 7.46 (dd, J=4.1, 4.1, 1H),4.71 (br s, 1H), 4.08 (br s, 1H), 3.08 (dd, J=15.0, 5.0, 1H), 2.91 (t,J=2.4, 2H), 2.63-2.57 (m, 1H), 2.12-2.08 (m, 1H), 2.00-1.94 (m, 1H),1.46 (s, 9H).

B. This compound was prepared according to the methods described inExample A, Step F. The crude product was used without furtherpurification. MS (ESI): exact mass calculated for C₁₆H₁₆N₄, 264.16; m/zfound, 265.30 [M+H]⁺.

Example G

2-Naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine

This compound was prepared according to methods described for Example A,Steps E and F. The crude product was used without further purification.MS (ESI): exact mass calculated for C₁₇H₁₇N₃, 263.14; m/z found, 264.3[M+H]⁺. ¹H NMR (9:1 mixture of isomers; 500 MHz, CDCl₃): 7.93-7.89 (m,3.5H), 7.55-7.46 (m, 7H), 3.30-3.27 (m, 1H), 3.00-2.95 (m, 2H),2.88-2.85 (m, 1H), 2.46-2.41 (m, 2H), 2.09-2.06 (m, 1H), 1.95-1.87 (m,0.6H), 1.81-1.77 (m, 1H).

Example H

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde

A. 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid. To asolution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidmethyl ester (1.5 g, 6.7 mmol) in a THF/H₂O mixture (1:1, 63 mL) wasadded 4 N LiOH (8.0 mL, 32 mmol) and the resulting solution was stirredat RT for 24 h. The solution was partially concentrated and diluted withH₂O (50 mL). The solution was acidified using concentrated HCl and asolid precipitated. The solid was collected via filtration, washed withH₂O and dried in vacuo to provide 0.79 g (60%) of the title compound asa white solid. MS (ESI): exact mass calculated for C₉H₇NO₃S, 209.01; m/zfound, 210.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.65-7.61 (m, 2H), 7.40(d, J=8.1, 1H), 3.48 (s, 2H).

B. 6-Hydroxymethyl-4H-benzo[1,4]thiazin-3-one. To a 0° C. suspension of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (400 mg, 2mmol) in THF (19 mL) was added Et₃N (0.32 mL, 2 mmol) and the resultingsolution was treated with iso-butylchloroformate (0.3 mL, 2 mmol). Theresulting suspension was stirred at 0° C. for 2 h, filtered and thesolid was washed with THF. The filtrate was cooled to 0° C., treatedwith NaBH₄ (150 mg, 4.3 mmol) and slowly treated with H₂O (10 mL). Theresulting suspension was warmed to RT and stirred for 18 h. Thesuspension was neutralized using 1 N HCl and diluted with H₂O (100 mL).The organic layer was extracted with EtOAc (3×200 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated. Theresulting residue was purified on SiO₂ (0-10% CH₃OH/CH₂Cl₂) to provide330 mg (89%) of the title compound as a white solid. MS (ESI): exactmass calculated for C₉H₉NO₂S, 195.04; m/z found, 196.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 7.26 (d, J=7.9, 1H), 7.01-6.98 (m, 2H), 4.55 (s, 2H),3.40 (s, 2H).

C. To a solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (360 mg,1.8 mmol) in THF/CHCl₃ (2:1, 18 mL) was added MO₂ (1.6 g, 18 mmol) andthe resulting suspension was heated to 70° C. and stirred for 4 h. Thesuspension was filtered through diatomaceous earth and the filtrate wasconcentrated. The resulting solid was triturated with EtOAc/hexanes(1:1) and a minimal amount of CH₃OH to provide 200 mg (56%) of the titlecompound as a tan solid. MS (ESI): exact mass calculated for C₉H₇NO₂S,193.02; m/z found, 194.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.94 (s, 1H),8.78 (br s, 1H), 7.54-7.49 (m, 2H), 7.37 (d, J=1.5, 1H), 3.52 (s, 2H).

Example I

3,4-Dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde

A. (3,4-Dihydro-2H-benzo[1,4]thiazin-6-yl)-methanol. To a solution of3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester(750 mg, 3.4 mmol) in Et₂O (32 mL) was added LiAlH₄ (240 mg, 6.3 mmol)and the resulting suspension was stirred at RT for 24 h. The reactionmixture was cooled to 0° C. and treated with H₂O (0.5 mL), 15% aq. NaOH(0.5 mL), and H₂O (1.5 mL). The resulting suspension was filtered. Thefiltrate was concentrated to provide 340 mg (58%) of the title compoundas an amber oil. MS (ESI): exact mass calculated for C₉H₁₁NOS, 181.06;m/z found, 182.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.96 (d, J=7.9, 1H),6.60 (dd, J=7.9, 1.6, 1H), 6.49 (d, J=7.9, 1H), 4.52 (s, 2H), 3.65-3.62(m, 2H), 3.06-3.04 (m, 2H).

B. This compound was prepared according to the methods described inExample H, Step C. MS (ESI): exact mass calculated for C₉H₉NOS, 179.04;m/z found, 180.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.79 (s, 1H),7.14-7.08 (m, 2H), 6.95 (d, J=1.6, 1H), 3.67-3.64 (m, 2H), 3.12-3.10 (m,2H).

Example J

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde

A. 2,4-Difluoro-benzoic acid ethyl ester. Into a solution of2,4-difluorobenzoic acid (36.0 g, 228 mmol) in EtOH (250 mL) was bubbledHCl_((g)) for 15 min. The solution was heated to 80° C. and stirred for24 h. The solution was partially concentrated and diluted with H₂O (300mL). The aqueous layer was extracted with EtOAc (3×300 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated to provide27.2 g (76%) of the title compound as a clear oil. MS (ESI): exact masscalculated for C₉H₈F₂O₂, 186.05; m/z not found. ¹H NMR (400 MHz, CDCl₃):8.01-7.95 (m, 1H), 6.95-6.85 (m, 2H), 4.39 (q, J=7.1, 2H), 1.39 (t,J=7.1, 3H).

B. 2,4-Difluoro-5-nitro-benzoic acid ethyl ester. To2,4-difluoro-benzoic acid ethyl ester (6.4 g, 34 mmol) at 0° C. wasadded HNO₃/H₂SO₄ (1:1, 10 mL). The resulting solution was allowed towarm to RT and was stirred for 18 h. The reaction mixture waspartitioned between H₂O and CH₂Cl₂ (400 mL). The organic layer waswashed with brine (200 mL), dried (MgSO₄), filtered and concentrated toprovide 7.0 g (88%) of the title compound as a white solid. MS (ESI):exact mass calculated for C₉H₇F₂NO₄, 231.03; m/z not found. ¹H NMR (400MHz, CDCl₃): 8.78 (dd, J=8.3, 7.3, 1H), 7.14 (t, J=9.9, 1H), 4.44 (q,J=7.2, 2H), 1.42 (t, J=7.2, 3H).

C. 4-Ethoxycarbonylmethylsulfanyl-2-fluoro-5-nitro-benzoic acid ethylester. To a solution of 2,4-difluoro-5-nitro-benzoic acid ethyl ester(7.0 g, 0.030 mol) in CH₂Cl₂ (125 mL) was added Et₃N (5.0 mL, 36 mmol)at 0° C. Following the addition of ethyl 2-mercaptoacetate (3.30 mL,30.3 mmol), the solution was warmed to RT and stirred for 18 h. Thereaction mixture was partitioned between H₂O and CH₂Cl₂ (400 mL). Theorganic layer was washed with 0.05 M HCl (200 mL), brine (200 mL), dried(MgSO₄), filtered and concentrated to provide 9.6 g (96%) of the titlecompound as a tan solid. MS (ESI): exact mass calculated forC₁₃H₁₄FNO₆S, 331.05; m/z not found. ¹H NMR (500 MHz, CDCl₃): 8.88 (d,J=6.9, 1H), 7.14 (d, J=11.4, 1H), 4.41 (q, J=7.2, 2H), 4.29 (q, J=7.2,2H), 3.75 (s, 2H), 1.40 (t, J=7.2, 3H), 1.29 (t, J=7.2, 3H).

D. 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidethyl ester. To a solution of4-ethoxycarbonylmethylsulfanyl-2-fluoro-5-nitro-benzoic acid ethyl ester(2.7 g, 8.2 mmol) in acetic acid (50 mL) was added iron (4.8 g, 86 mmol)and the suspension was heated to 80° C. and stirred for 2 h. Thereaction mixture was filtered and the filtrate was partitioned betweenH₂O and EtOAc (1×200 mL; 2×100 mL). The combined organic layers werewashed with brine (300 mL), dried (MgSO₄), filtered and concentrated toprovide 1.7 g (82%) of the title compound as a tan solid. MS (ESI):exact mass calculated for C₁₁H₁₀FNO₃S, 255.04; m/z found, 256.3 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.75 (br s, 1H), 7.46 (d, J=6.1, 1H), 7.12 (d,J=10.4, 1H), 4.40 (q, J=7.1, 2H), 3.48 (s, 2H), 1.38 (t, J=7.1, 3H).

E. 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid.This compound was prepared according to the methods described in ExampleH, Step A. MS (ESI): exact mass calculated for C₉H₆FNO₃S, 227.01; m/zfound, 228.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.25 (br s, 1H), 10.72(s, 1H), 7.46 (d, J=6.7, 1H), 7.38 (d, J=10.6, 1H), 3.55 (s, 2H).

F. 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one. This compoundwas prepared according to the methods described in Example H, Step B. MS(ESI): exact mass calculated for C₉H₈FNO₂S, 213.03; m/z not found. ¹HNMR (500 MHz, CDCl₃/CD₃OD, 9:1): 6.94 (d, J=7.8, 1H), 6.92 (d, J=5.1,1H), 4.61 (s, 2H), 3.33 (s, 2H).

G. This compound was prepared according to the methods described inExample H, Step C. MS (ESI): exact mass calculated for C₉H₆FNO₂S,211.01; m/z found, 212.5 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 10.78 (br s,1H), 10.09 (br s, 1H), 7.49 (d, J=10.5, 1H), 7.32 (d, J=6.3, 1H), 3.56(s, 2H).

Example K

7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

The title compound was prepared according to the procedures described inExample J, Steps A through E, starting with 2-chloro-4-fluoro-benzoicacid.

A. 2-Chloro-4-fluoro-benzoic acid ethyl ester. MS (ESI): exact masscalculated for C₉H₈ClFO₂, 202.02; m/z not found. ¹H NMR (400 MHz,CDCl₃): 7.89 (dd, J=8.8, 6.2, 1H), 7.19 (dd, J=8.5, 2.5, 1H), 7.05-7.00(m, 1H), 4.39 (q, J=7.1, 2H), 1.40 (t, J=7.1, 3H).

B. 2-Chloro-4-fluoro-5-nitro-benzoic acid ethyl ester. MS (ESI): exactmass calculated for C₉H₇ClFNO₄, 247.00; m/z not found. ¹H NMR (500 MHz,CDCl₃): 8.48 (d, J=8.0, 1H), 7.35 (d, J=10.3, 1H), 4.31 (q, J=7.1, 2H),1.31 (t, J=7.1, 3H).

C. 2-Chloro-4-ethoxycarbonylmethylsulfanyl-5-nitro-benzoic acid ethylester. MS (ESI): exact mass calculated for C₁₃H₁₄ClNO₈S, 347.02; m/z notfound. ¹H NMR (500 MHz, CDCl₃): 8.78 (s, 1H), 7.57 (s, 1H), 4.42 (q,J=7.1, 2H), 4.25 (q, J=7.1, 2H), 3.77 (s, 2H), 1.41 (t, J=7.1, 3H), 1.30(t, J=7.1, 3H).

D. 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidethyl ester. MS (ESI): exact mass calculated for C₁₁H₁₀ClNO₃S, 271.01;m/z not found. ¹H NMR (400 MHz, CDCl₃): 9.14 (s, 1H), 7.41 (s, 2H), 4.40(q, J=6.9, 2H), 3.47 (s, 2H), 1.40 (t, J=6.9, 3H).

E. 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid.MS (ESI): exact mass calculated for C₉H₆ClNO₃S, 242.98; m/z not found.¹H NMR (400 MHz, CDCl₃): 10.67 (s, 1H), 7.38 (s, 1H), 7.23 (s, 1H), 3.49(s, 2H).

Example L

3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde

A. 6-Bromo-2-nitro-pyridin-3-ol. To a solution of3-hydroxy-2-nitropyridine (20 g, 140 mmol) in CH₃OH (400 mL) was added asolution of 25% NaOCH₃ in CH₃OH (33.0 mL, 153 mmol). After stirring atRT for 30 min, the reaction mixture was cooled to 0° C. and Br₂ (7.2 mL,140 mmol) added slowly. The mixture was stirred for 30 min, and then wasquenched with glacial acetic acid (2.5 mL). The solvent was removedunder reduced pressure. A portion of the crude material was purified onSiO₂ (50% EtOAc/hexanes) to provide the title compound as a white solid.MS (ESI): exact mass calculated for C₅H₃BrN₂O₃, 217.93; m/z not found.¹H NMR (400 MHz, CDCl₃): 10.24 (s, 1H), 7.74 (d, J=8.6, 1H), 7.54 (d,J=8.6, 1H).

B. (6-Bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester. To asuspension of 6-bromo-2-nitro-pyridin-3-ol (3.07 g, 14.0 mmol) inacetone (20 mL) was added K₂CO₃ (3.93 g, 28.0 mmol) and ethylbromoacetate (1.55 mL, 14.0 mmol). The mixture was heated to reflux andstirred for 20 h. The resulting suspension was cooled to RT, dilutedwith Et₂O (100 mL) and filtered. The filtrate was concentrated to afford3.14 g (74%) of the title compound, which was used without furtherpurification. MS (ESI): exact mass calculated for C₉H₉BrN₂O₅, 303.97;m/z found, 305.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.67 (d, J=8.6, 1H),7.35 (d, J=8.7, 1H), 4.78 (s, 2H), 4.27 (q, J=7.1, 2H), 1.30 (t, J=8.5,3H).

C. 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of(6-bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester (3.14 g, 10.3mmol) in glacial acetic acid (12.4 mL) was added iron powder (1.67 g,29.9 mmol). The suspension was heated to 90° C. and stirred for 6 h,after which it was cooled to RT and diluted with EtOAc (50 mL). Themixture was filtered through a pad of SiO₂ and the filtrate wasconcentrated. Recrystallization from CH₃OH provided 1.32 g (57%) of thetitle compound as a solid. MS (ESI): exact mass calculated forC₇H₅BrN₂O₂, 227.95; m/z found, 228.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.98 (d, J=5.3, 1H), 7.16-7.09 (m, 1H), 6.98 (dd, J=8.0, 4.9, 1H), 4.68(d, J=1.4, 2H).

D. 6-Styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (3.2 g, 14 mmol) in1,4-dioxane (80 mL) was added trans-2-phenylvinylboronic acid (2.1 g, 14mmol). After the reaction mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium(0) (0.129 g, 0.112 mmol) and asolution of K₂CO₃ (3.7 g, 27 mmol) in H₂O (10.7 mL) were added. Thereaction was heated at reflux for 17 h, then cooled to RT, and dilutedwith EtOAc (300 mL). The organic layer was separated, washed with H₂O(300 mL), brine (300 mL), dried (Na₂SO₄), and concentrated. The solidresidue was purified on SiO₂ (5-10% EtOAc/CHCl₃) to provide 1.5 g (43%)of the title compound as a solid. MS (ESI): exact mass calculated forC₁₅H₁₂N₂O₂, 252.09; m/z found, 253.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.53-7.00 (m, 9H), 4.66 (d, J=6.9, 2H).

E. To a solution of 6-styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one (757 mg,3.00 mmol) in CH₂Cl₂ (128 mL) was bubbled ozone at −78° C. with stirringuntil a pale blue color appeared. The excess ozone was removed bybubbling oxygen through the reaction mixture for 15 min. Me₂S (1.0 mL,14 mmol) was added, and the reaction was stirred at −78° C. for 3 h andthen at RT for 24 h. The solvent was concentrated and the residue wastriturated with Et₂O (100 mL). The solid collected from filtration ofthe suspension was washed with additional Et₂O and dried in vacuo toprovide 340 mg (63% crude) of a solid, which was used without furtherpurification. MS (ESI): exact mass calculated for C₈H₆N₂O₃, 178.04; m/zfound, 179.2 [M+H]⁺.

Example M

7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde

To a solution of 6-fluoroveratraldehyde (1.2 g, 6.2 mmol) in CH₂Cl₂ (62mL) was added BBr₃ (6.2 mL, 62 mmol) and the solution was stirred at RTfor 4 h. The solution was then cooled to 0° C., diluted with EtOAc (120mL) and slowly treated with H₂O (60 mL). The organic layer was washedwith brine (2×100 mL), dried, filtered and concentrated to provide thedesired catechol intermediate as a dark brown solid (1.0 g, 6.4 mmol).This solid was immediately treated with 1,2-dibromoethane (0.60 mL, 7.1mmol) and heated to 100° C. The suspension was treated with NaOH (0.50g, 13 mmol) in H₂O (30 mL) dropwise over 1 h and stirred at 100° C. for2 days. The suspension was then filtered. The collected solid wasre-suspended in CHCl₃ and filtered. The filtrate was concentrated toprovide 0.22 g (19%) of the title compound as a tan solid. MS (ESI):exact mass calculated for C₉H₇FO₃, 182.04; m/z not found. ¹H NMR (500MHz, CDCl₃): 10.21 (s, 1H), 7.35 (d, J=6.7, 1H), 6.66 (d, J=10.9, 1H),4.33 (m, 2H), 4.25 (m, 2H).

Example N

7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid

To a solution of KMnO₄ (0.35 g, 2.2 mmol) in H₂O (11 mL) at 80° C. wasadded 7-fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.20 g, 1.1mmol). The resulting suspension was stirred at 100° C. for 24 h. Thereaction mixture was filtered and the solids were washed with H₂O (30mL). The filtrate was acidified with concentrated HCl, which led to theformation of a white precipitate, which was collected, washed with H₂Oand dried in vacuo to provide 0.12 g (57%) of the title compound as awhite solid. MS (ESI): exact mass calculated for C₉H₇FO₄, 198.03; m/znot found. ¹H NMR (400 MHz, DMSO-d₆): 12.95 (s, 1H), 7.29 (d, J=7.2,1H), 6.87 (d, J=11.6, 1H), 4.34-4.31 (m, 2H), 4.27-4.24 (m, 2H).

Example O

8-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde

This compound was prepared according to methods described for Example M.¹H NMR (500 MHz, CDCl₃): 9.78 (d, J=2.0, 1H), 7.22-7.26 (m, 2H),4.38-4.41 (m, 2H), 4.33-4.35 (m, 2H).

Example P

8-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid

This compound was prepared according to methods described for Example N.¹H NMR (500 MHz, DMSO-d₆): 12.98 (s, 1H), 7.27 (d, J=11.0, 1H), 7.22 (m,1H), 4.31-4.36 (m, 4H).

Example Q

7-Chloro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde

This compound was prepared according to methods described for Example M.¹H NMR (500 MHz, CDCl₃): 10.21 (s, 1H), 7.45 (s, 1H), 6.94 (s, 1H),4.31-4.33 (m, 2H), 4.26-4.28 (m, 2H).

Example R

5,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

A. Ethyl 2,4,6-trifluorobenzoate. A suspension of 2,4,6-trifluorobenzoicacid (4.93 g, 28.0 mmol) in thionyl chloride (15 mL) was heated atreflux for 1 h. After cooling, the thionyl chloride was removed invacuo, and final traces of thionyl chloride were azeotropically removedwith CH₂Cl₂ leaving the acid chloride as a pale yellow liquid. To asolution of EtOH (3.3 mL, 56 mmol) and pyridine (4.5 mL, 56 mmol) inCH₂Cl₂ (20 mL) at RT was added a solution of the acid chloride in CH₂Cl₂(5 mL) via pipet. The mixture was allowed to stir for 2 h at RT and thenwas poured into 1 N HCl and extracted with CH₂Cl₂. The organic layer waswashed with 1 N HCl (1×) and satd. aq. NaHCO₃ (2×). The organic layerwas dried (Na₂SO₄) and concentrated to provide 3.93 g (69%) of the titlecompound as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): 6.72 (m, 1H),4.41 (q, J=7.2, 2H), 1.39 (t, J=7.2, 3H).

B. Ethyl 3-nitro-2,4,6-trifluorobenzoate. To a suspension of ethyl2,4,6-trifluorobenzoate (3.93 g, 19.2 mmol) in conc. H₂SO₄ at 0° C. wasadded conc. HNO₃ (70% HNO₃) dropwise via pipet. After the addition wascomplete, the reaction was allowed to warm to RT and stir for 4 h. Thebiphasic mixture was poured into H₂O and extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried (Na₂SO₄) and concentrated to provide4.71 g (98%) of the title compound as a yellow solid. ¹H NMR (400 MHz,CDCl₃): 6.96 (ddd, J=9.2, 9.2, 2.2, 1H), 4.45 (q, J=7.2, 2H), 1.40 (t,J=7.2, 3H).

C. 4-Ethoxycarbonylmethylsulfanyl-2,6-difluoro-3-nitro-benzoic acidethyl ester. This compound was prepared according to methods describedfor Example J, Step C. MS (ESI): exact mass calculated for C₁₃H₁₃F₂NO₆S,349.0; m/z found, 350 [M+H]⁺, 372 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): 7.17(dd, J=10.0, 1.9, 1H), 4.44 (q, J=7.1, 2H), 4.24 (q, J=7.2, 2H), 3.73(s, 2H), 1.39 (t, J=7.1, 3H), 1.29 (t, J=7.1, 3H).

D. 5,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid ethyl ester. This compound was prepared according to methodsdescribed for Example J, Step D. MS (ESI): exact mass calculated forC₁₁H₉F₂NO₃S, 273.0; m/z found, 274 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.89(br s, 1H), 6.95 (d, J=8.8, 1H), 4.42 (q, J=7.0, 2H), 3.49 (s, 2H), 1.39(t, J=7.0, 3H).

E. This compound was prepared according to methods described for ExampleH, Step A. The crude product was used without further purification. MS(ESI): exact mass calculated for C₉H₅F₂NO₃S, 245.0; m/z found, 246[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.10 (dd, J=9.3, 1.8, 1H), 3.52 (s,2H).

Example S

3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid

A. 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methylester. To a suspension of 4-hydroxy-3-nitro-benzoic acid methyl ester(10.0 g, 50.7 mmol) in acetone (72 mL) was added K₂CO₃ (14.0 g, 101mmol) followed by ethyl bromoacetate (5.60 mL, 50.7 mmol). The mixturewas heated to 55° C. and stirred for 18 h. The mixture was allowed tocool to RT, diluted with Et₂O (75 mL) and filtered. The filtrate wasconcentrated to provide 14.9 g of a solid which was dissolved in glacialacetic acid (63 mL). To this solution was added Fe powder (8.50 g, 151mmol). The mixture was heated to 117° C. and stirred for 5.5 h, at whichtime it was cooled to RT and diluted with EtOAc (70 mL). The mixture wasfiltered through a pad of SiO₂, eluting with EtOAc. The filtrate wasconcentrated to give a solid, which was recrystallized from MeOH toprovide 9.2 g (84%) of the title compound as a tan solid. MS (ESI):exact mass calculated for C₁₀H₉NO₄, 207.05; m/z found, 208.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 8.06 (br s, 1H), 7.69 (dd, J=8.4, 7.7, 1H), 7.51(d, J=1.9, 1H), 7.00 (d, J=8.4, 1H), 4.69 (s, 2H), 3.90 (s, 3H).

B. To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (3.13 g, 15.1 mmol) in THF/H₂O (3:1; 76 mL) was addeda LiOH (4 M in H₂O; 19.0 mL, 75.5 mmol), and the solution was stirred atRT for 24 h. The solution was concentrated, diluted with H₂O (50 mL),and acidified to pH<1 with conc. HCl. The resulting precipitate wascollected by filtration afforded 7.6 g of the title compoundcontaminated with excess HCl and H₂O. MS (ESI): exact mass calculatedfor C₉H₇NO₄, 193.04; m/z found, 194.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):10.85 (br s, 1H), 7.50-7.47 (m, 2H), 6.99 (d, J=8.3, 1H), 4.63 (s, 2H).

Example T

3-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid

This compound was prepared according to methods described for Example H,Step A. The crude product was used without further purification. MS(ESI): exact mass calculated for C₁₀H₆F₃NO₃S, 277.0; m/z found, 278.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.91 (br s, 1H), 7.59 (s, 1H), 7.20 (s,1H), 3.45 (s, 2H).

Example U

7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

A. 2-Bromo-4-fluoro-benzoic acid methyl ester. To a solution of2-bromo-4-fluoro-benzoic acid (10.95 g, 50 mmol) in toluene/MeOH (3:1;200 mL) was added trimethylsilyldiazomethane (2 M in hexanes; 36 mL,71.7 mmol) at RT for 3 h. The mixture was diluted with EtOAc (300 mL)and washed sequentially with satd. aq. NaHCO₃ (50 mL) and brine (50 mL),dried (MgSO₄), and concentrated to provide 11.5 g (99%) of the crudematerial which was used in the next step without further purification.¹H NMR (500 MHz, CDCl₃): 7.86 (dd, J=8.8, 6.0, 1H), 7.39 (dd, J=8.3,2.5, 2H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).

B. 2-Bromo-4-fluoro-5-nitro-benzoic acid methyl ester. To conc. fumingH₂SO₄ (8 mL) at 0° C. was added conc. fuming HNO₃ (8 mL) and the mixtureallowed to stand for 5 min. To a solution of 2-bromo-4-fluoro-benzoicacid methyl ester (9.32 g, 40 mmol) at 0° C., the mixture of acids wasadded dropwise over 30 min. The mixture was allowed to warm to RT andwas stirred for 18 h. The mixture was poured into ice water, dilutedwith EtOAc, and treated with 6 N NaOH. The aqueous layer was extractedwith EtOAc (3×300 mL). The combined organic layers were washed withbrine (200 mL), dried (MgSO₄), and concentrated. The crude material waspurified on SiO₂ (0-25% EtOAc/hexanes) to provide 4.9 g (43%) of thetitle compound. ¹H NMR (500 MHz, CDCl₃): 8.61 (d, J=8.0, 1H), 7.66 (d,J=10.0, 1H), 3.91 (s, 3H).

C. 2-Bromo-4-ethoxycarbonylmethylsulfanyl-5-nitro-benzoic acid methylester. To a 0° C. solution of 2-bromo-4-fluoro-5-nitro-benzoic acidmethyl ester (4.8 g, 17.3 mmol) in CH₂Cl₂ (87 mL) was added Et₃N,followed by mercapto-acetic acid ethyl ester, and the resulting mixturewas stirred at RT for 4 h. The mixture was diluted with EtOAc (250 mL),washed with brine (50 mL), dried (MgSO₄), and concentrated. The crudematerial was purified on SiO₂ (0-35% EtOAc/hexanes) to provide 5 g (77%)of the title compound. ¹H NMR (500 MHz, CDCl₃): 8.75 (s, 1H), 7.79 (s,1H), 4.24 (q, J=7.2, 2H), 3.96 (s, 3H), 3.78 (s, 2H), 1.30 (t, J=7.2,3H).

D. 7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidmethyl ester. This compound was prepared according to methods describedfor Example J, Step D, to provide 2.26 g (94%) as the crude materialwhich was used without further purification. MS (ESI): exact masscalculated for C₁₀H₈BrNO₃S, 300.94; m/z found, 302.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 9.15 (s, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 3.91 (s, 3H),3.46 (s, 2H).

E. This compound was prepared according to methods described for ExampleH, Step A, to provide 0.17 g (60%) of the title compound. MS (ESI):exact mass calculated for C₉H₆BrNO₃S, 286.93; m/z found, 285.8 [M−H]⁺.¹H NMR (500 MHz, DMSO-d₆): 13.35 (br s, 1H), 10.73 (s, 1H), 7.66 (s,1H), 7.36 (s, 1H), 3.51 (s, 2H).

Example 1

2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

To a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (44 mg,0.24 mmol) and2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(48 mg, 0.16 mmol) in DMF (1 mL) was added HOBT (1-hydroxybenzotriazole;33 mg, 0.24 mmol) and EDC; 47 mg, 0.24 mmol). The reaction mixture wasstirred for 1.5 h at RT. The reaction mixture was diluted with CH₃OH andpurified directly by basic reverse phase HPLC to provide 22 mg (30%) ofthe title compound. MS (ESI): exact mass calculated for C₂₅H₂₃N₅O₄,457.18; m/z found, 458.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.14 (s, 1H),8.76 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.16 (d, J=5.1, 1H), 7.31-7.28(m, 1H), 7.26-7.23 (m, 1H), 7.17 (d, J=9.1, 1H), 6.86 (d, J=8.4, 1H),6.13 (d, J=7.7, 1H), 4.54-4.51 (m, 1H), 4.27-4.24 (m, 4H), 4.07 (s, 3H),3.19 (dd, J=15.5, 5.1, 1H), 2.99-2.96 (m, 2H), 2.66 (dd, J=15.5, 7.7,1H), 2.21-2.16 (m, 1H), 2.10-2.03 (m, 1H).

The compounds in Examples 2-32 were prepared according to the methodsdescribed for Example 1, with adjustments where noted.

Example 2

7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

Once the reaction was complete, the reaction mixture was diluted withEtOAc (20 mL) and 1 N NaOH (10 mL). The aqueous layer was extracted withEtOAc (3×20 mL). The combined organic layers were washed with brine,dried (MgSO₄) and concentrated. The crude was purified on SiO₂ (0-100%EtOAc/hexanes) to provide 64 mg (69%) of the title compound. MS (ESI):exact mass calculated for C₂₅H₂₂FN₅O₄, 475.17; m/z found, 476.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 9.15 (s, 1H), 8.78 (d, J=5.1, 1H), 8.26 (d,J=9.1, 1H), 8.17 (d, J=5.0, 1H), 7.62 (d, J=7.6, 1H), 7.19 (d, J=9.1,1H), 6.77 (dd, J=14.2, 7.4, 1H), 6.61 (d, J=12.5, 1H), 4.57-4.52 (m,1H), 4.30-4.28 (m, 2H), 4.25-4.24 (m, 2H), 4.09 (s, 3H), 3.21 (dd,J=15.4, 5.1, 1H), 3.00 (t, J=6.6, 2H), 2.69 (dd, J=15.5, 8.0, 1H),2.26-2.20 (m, 1H), 2.09-2.02 (m, 1H).

Example 3

3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₅N₅O₄, 471.19; m/z found, 472.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.15 (s, 1H), 8.77 (d, J=5.1, 1H), 8.25(d, J=9.1, 1H), 8.17 (d, J=5.1, 1H), 7.37-7.32 (m, 2H), 7.18 (d, J=9.1,1H), 6.96 (d, J=8.3, 1H), 6.12 (d, J=7.8, 1H), 4.55-4.52 (m, 1H),4.27-4.21 (m, 4H), 4.08 (s, 3H), 3.19 (dd, J=15.5, 5.0, 1H), 2.99-2.97(m, 2H), 2.67 (dd, J=15.5, 7.5, 1H), 2.22-2.17 (m, 3H), 2.09-2.05 (m,1H).

Example 4

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

HPLC: R_(t)=6.29 min. MS (ESI): exact mass calculated for C₂₅H₂₂N₆O₃S,486.15; m/z found, 487.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 10.13 (s, 1H),9.72 (d, J=5.1, 1H), 9.22 (d, J=9.1, 1H), 9.12 (d, J=5.1, 1H), 8.96 (brs, 1H), 8.34 (d, J=1.7, 1H), 8.30 (d, J=8.1, 1H), 8.22 (dd, J=8.1, 1.7,1H), 8.19 (d, J=9.1, 1H), 7.13 (d, J=7.1, 1H), 5.56-5.52 (m, 1H), 5.03(s, 3H), 4.41 (s, 2H), 4.17 (dd, J=15.5, 4.9, 1H), 3.99-3.91 (m, 2H),3.68-3.63 (m, 1H), 3.18-3.12 (m, 2H).

Example 5

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

Once the reaction was complete, 1 N NaOH (10 mL) was added to thereaction mixture and a precipitate formed. The solids were filtered,washed with 1 N HCl, 1 N NaOH, and H₂O. Drying in vacuo gave 42 mg (76%)of the title compound. MS (ESI): exact mass calculated for C₂₅H₂₁FN₆O₃S,504.14; m/z found, 505.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 10.66 (br s,1H), 9.12 (br s, 1H), 8.76 (d, J=5.1, 1H), 8.38 (d, J=6.6, 1H), 8.31 (d,J=9.1, 1H), 8.08 (d, J=5.1, 1H), 7.37-7.33 (m, 2H), 7.17 (d, J=6.6, 1H),4.20-4.15 (m, 1H), 4.04 (s, 3H), 3.49 (s, 2H), 3.03 (dd, J=15.4, 5.1,1H), 2.92-2.86 (m, 1H), 2.83-2.78 (m, 1H), 2.60 (dd, J=15.4, 9.4, 1H),2.07-2.03 (m, 1H), 1.92-1.85 (m, 1H).

Example 6

7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

The crude material was purified on SiO₂ (0-10% CH₃OH/CH₂Cl₂, then50-100% EtOAc/hexanes). MS (ESI): exact mass calculated forC₂₅H₂₁ClN₆O₃S, 520.11; m/z found, 521.3 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 10.72 (br s, 1H), 9.14 (s, 1H), 8.77 (d, J=5.0, 1H), 8.60 (d,J=7.7, 1H), 8.32 (d, J=9.1, 1H), 8.09 (d, J=5.0, 1H), 7.48 (s, 1H), 7.35(d, J=9.1, 1H), 6.96 (s, 1H), 4.18-4.13 (m, 1H), 4.06 (s, 3H), 3.48 (s,2H), 3.04 (dd, J=16.0, 5.0, 1H), 2.93-2.88 (m, 1H), 2.84-2.77 (m, 1H),2.62-2.60 (m, 1H), 2.06-2.05 (m, 1H), 1.91-1.83 (m, 1H).

Example 7

4,6-Difluoro-1H-indole-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₀F₂N₆O₂, 474.16; m/z found,475.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.43 (s, 1H), 9.19 (s, 1H), 8.80(d, J=5.0, 1H), 8.28 (d, J=9.1, 1H), 8.19 (d, J=5.1, 1H), 7.21 (d,J=9.1, 1H), 6.94 (d, J=8.8, 1H), 6.89 (s, 1H), 6.65 (dt, J=9.9, 1.8,1H), 6.25 (d, J=7.7, 1H), 4.63-4.57 (m, 1H), 4.10 (s, 3H), 3.25 (dd,J=15.4, 5.1, 1H), 3.03 (dd, J=6.5, 6.5, 2H), 2.74 (dd, J=15.3, 7.6, 1H),2.29-2.22 (m, 1H), 2.16-2.10 (m, 1H).

Example 8

1H-Benzoimidazole-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₄H₂₁N₇O₂, 439.18; m/z found, 440.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃ with a drop of CD₃OD): 9.16 (s, 1H), 8.75(d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.68-7.63 (m,2H), 7.36 (br s, 2H), 7.26 (d, J=9.1, 1H), 4.50 (br s, 1H), 4.13 (t,3H), 3.25 (dd, J=15.5, 5.2, 1H), 3.18-3.08 (m, 2H), 3.04-2.98 (m, 1H),2.84 (dd, J=15.5, 8.7, 1H), 2.36-2.31 (m, 1H), 2.19-2.11 (m, 1H).

Example 9

2-(1H-Indol-2-yl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-2-oxo-acetamide

MS (ESI): exact mass calculated for C₂₆H₂₂N₆O₃, 466.18; m/z found, 467.3[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.16 (s, 1H), 9.14 (d, J=3.1, 1H), 8.88(s, 1H), 8.80 (d, J=5.0, 1H), 8.42 (d, J=7.9, 1H), 8.28 (d, J=9.1, 1H),8.18 (d, J=5.0, 1H), 7.68 (d, J=8.0, 1H), 7.47 (d, J=7.5, 1H), 7.37-7.33(m, 2H), 7.20 (d, J=9.1, 1H), 4.43-4.38 (m, 1H), 4.11 (s, 3H), 3.20 (dd,J=15.4, 5.2, 1H), 3.07-2.97 (m, 2H), 2.73 (dd, J=15.4, 8.2, 1H),2.27-2.21 (m, 1H), 2.12-2.05 (m, 1H).

Example 10

N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-phenyl-acrylamide

The crude material was purified on SiO₂ (0-10% CH₃OH/EtOAc) to provide37 mg (45%) of the title compound as a white solid. MS (ESI): exact masscalculated for C₂₅H₂₃N₅O₂, 425.19; m/z found, 426.8 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 9.07 (br s, 1H), 8.68 (d, J=5.2, 1H), 8.20 (d, J=9.1, 1H),8.07 (d, J=5.2, 1H), 7.59-7.49 (m, 3H), 7.35-7.30 (m, 3H), 7.22 (d,J=9.1, 1H), 6.59 (d, J=15.7, 1H), 4.32-4.29 (m, 1H), 4.08 (s, 3H), 3.11(dd, J=15.3, 5.2, 1H), 3.01-2.91 (m, 2H), 2.63 (dd, J=15.5, 9.1, 1H),2.20-2.17 (m, 1H), 1.97-1.95 (m, 1H).

Example 11

3-(3,5-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

The reaction mixture was stirred overnight instead of 1.5 h. MS (ESI):exact mass calculated for C₂₅H₂₁F₂N₅O₂, 461.17; m/z found, 462.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 9.10 (s, 1H), 8.74 (d, J=5.1, 1H), 8.25 (d,J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.55 (d, J=15.5, 1H), 7.18 (d, J=9.1,1H), 7.00-6.95 (m, 2H), 6.79-6.75 (m, 1H), 6.42 (d, J=15.5, 1H), 6.02(d, J=7.9, 1H), 4.55-4.51 (m, 1H), 4.06 (s, 3H), 3.14 (dd, J=15.3, 4.7,1H), 3.00-2.92 (m, 2H), 2.66 (dd, J=15.6, 6.8, 1H), 2.16-2.03 (m, 2H).

Example 12

3-(3-Chloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

The reaction mixture was stirred overnight instead of 1.5 h. MS (ESI):exact mass calculated for C₂₅H₂₂ClN₅O₂, 459.15; m/z found, 460.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃ with a drop of CD₃OD): 9.09 (s, 1H), 8.73 (d,J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.12 (d, J=5.1, 1H), 7.55 (d, J=9.3,1H), 7.50 (br s, 1H), 7.39-7.37 (m, 1H), 7.33-7.28 (m, 2H), 7.22 (d,J=9.1, 1H), 6.53 (d, J=15.7, 1H), 4.46-4.41 (m, 1H), 4.09 (s, 3H), 3.15(dd, J=15.4, 5.2, 1H), 3.03-2.93 (m, 2H), 2.66 (dd, J=15.6, 8.0, 1H),2.22-2.16 (m, 1H), 2.07-2.01 (m, 1H).

Example 13

3-(4-Fluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

The reaction mixture was stirred overnight instead of 1.5 h. MS (ESI):exact mass calculated for C₂₅H₂₂FN₅O₂, 443.18; m/z found, 444.3 [M+H]⁺.¹H NMR (600 MHz, CDCl₃ with a drop of CD₃OD): 9.12 (s, 1H), 8.74 (d,J=5.4, 1H), 8.26 (d, J=9.0, 1H), 8.13 (d, J=5.4, 1H), 7.58 (d, J=15.6,1H), 7.54-7.51 (m, 2H), 7.25 (d, J=9.0, 1H), 7.07 (t, J=8.4, 2H), 6.46(d, J=15.6, 1H), 4.43-4.41 (m, 1H), 4.11 (s, 3H), 3.16 (dd, J=15.0, 4.8,1H), 3.01-2.97 (m, 2H), 2.67 (dd, J=15.6, 8.4, 1H), 2.19-2.18 (m, 1H),2.03-2.02 (m, 1H).

Example 14

N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-(3-nitro-phenyl)-acrylamide

The reaction mixture was stirred overnight instead of 1.5 h. MS (ESI):exact mass calculated for C₂₅H₂₂N₆O₄, 470.17; m/z found, 471.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃ with a drop of CD₃OD): 9.11 (s, 1H), 8.73 (d,J=4.9, 1H), 8.39 (br s, 1H), 8.25 (d, J=9.1, 1H), 8.19 (d, J=8.2, 1H),8.12 (d, J=5.1, 1H), 7.83 (d, J=3.9, 1H), 7.66 (d, J=15.7, 1H), 7.58 (t,J=8.0, 1H), 7.24 (d, J=9.1, 1H), 6.71 (d, J=15.8, 1H), 4.43-4.40 (m,1H), 4.10 (s, 3H), 3.17 (dd, J=15.7, 5.1, 1H), 3.05-2.94 (m, 2H),2.24-2.21 (m, 1H), 2.07-1.99 (m, 1H).

Example 15

6-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carbonyl]-4H-benzo[1,4]thiazin-3-one

HPLC: R_(t)=5.85 min. MS (ESI): exact mass calculated for C₂₅H₂₂N₆O₃S,486.15; m/z found, 487.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.25-9.15 (m,1H), 8.79-8.75 (m, 1H), 8.28 (d, J=9.0, 1H), 8.22-8.12 (m, 1H),7.99-7.90 (m, 1H), 7.48-7.39 (m, 1H), 7.20 (d, J=9.1, 1H), 7.08 (dd,J=7.9, 1.6, 1H), 6.92 (d, J=1.6, 1H), 4.12-4.06 (m, 3H), 3.99-3.82 (m,2H), 3.69-3.60 (m, 2H), 3.47 (s, 2H), 3.25-3.21 (m, 1H), 2.99-2.90 (m,2H), 2.78-2.70 (m, 1H).

Example 16

2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₄N₄O₄, 456.18; m/z found, 457.5[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.08 (d, J=9.2,1H), 7.68 (s, 1H), 7.65 (d, J=2.8, 1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.36(d, J=4.7, 1H), 7.33-7.27 (m, 2H), 6.91 (d, J=8.4, 1H), 6.11 (d, J=7.8,1H), 4.58-4.55 (m, 1H), 4.33-4.27 (m, 4H), 3.91 (s, 3H), 3.21 (dd,J=15.5, 5.1, 1H), 3.03-3.00 (m, 2H), 2.67 (dd, J=15.5, 7.9, 1H),2.27-2.20 (m, 1H), 2.12-2.03 (m, 1H).

Example 17

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₃N₅O₃S, 485.15; m/z found,486.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.01 (d, J=5.6, 1H), 8.39 (d,J=9.4, 1H), 8.13 (d, J=2.5, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.62-7.60(m, 2H), 7.38-7.29 (m, 3H), 6.17 (d, J=7.6, 1H), 4.55-4.53 (m, 1H), 3.97(s, 3H), 3.46 (s, 2H), 3.27 (dd, J=15.7, 5.7, 1H), 3.06-3.03 (m, 2H),2.72-2.67 (m, 1H), 2.30-2.27 (m, 1H), 2.10-2.05 (m, 1H).

Example 18

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂FN₅O₃S, 503.14; m/z found,504.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.59 (s, 1H), 8.80 (d, J=4.7,1H), 8.08 (d, J=9.2, 1H), 8.01 (d, J=7.0, 1H), 7.70 (s, 1H), 7.65 (d,J=2.8, 1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.37 (d, J=4.7, 1H), 7.09 (d,J=11.5, 1H), 7.00 (dd, J=14.7, 7.8, 1H), 4.80-4.76 (m, 1H), 3.91 (s,3H), 3.46 (s, 2H), 3.26 (dd, J=15.7, 5.0, 1H), 3.12-2.96 (m, 2H), 2.76(dd, J=15.7, 7.3, 1H), 2.30-2.25 (m, 1H), 2.18-2.09 (m, 1H).

Example 19

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

This compound was a side product from the reaction that provided Example18. MS (ESI): exact mass calculated for C₂₆H₂₂FN₅O₃S, 503.14; m/z found,504.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.85 (d, J=4.6, 1H), 8.82 (s,1H), 8.09 (d, J=9.2, 1H), 7.86 (d, J=6.9, 1H), 7.67 (s, 1H), 7.43 (dd,J=9.2, 2.8, 1H), 7.31 (d, J=4.6, 1H), 7.11 (d, J=11.5, 1H), 7.07 (d,J=2.8, 1H), 6.90 (dd, J=14.6, 7.9, 1H), 4.74-4.70 (m, 1H), 3.84 (s, 3H),3.46 (s, 2H), 3.18 (dd, J=15.6, 5.1, 1H), 2.85-2.77 (m, 1H), 2.73-2.57(m, 2H), 2.19-2.16 (m 1H), 2.06-1.99 (m, 1H).

Example 20

7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

The crude material was purified on SiO₂ (0-10% CH₃OH/CH₂Cl₂, then50-100% EtOAc/hexanes). MS (ESI): exact mass calculated forC₂₆H₂₂ClN₅O₃S, 519.11; m/z found, 520.3 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 8.79 (d, J=4.7, 1H), 8.07 (d, J=9.2, 1H), 7.80 (s, 1H), 7.68(s, 1H), 7.62 (d, J=2.8, 1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.36 (s, 1H),7.34-7.33 (m, 2H), 6.59 (d, J=7.9, 1H), 4.63-4.60 (m, 1H), 3.90 (s, 3H),3.44 (s, 2H), 3.20 (dd, J=15.6, 4.8, 1H), 3.04-3.01 (m, 2H), 2.75 (dd,J=15.7, 7.1, 1H), 2.27-2.22 (m, 1H), 2.17-2.13 (m, 1H).

Example 21

1H-Indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₃N₅O₂, 437.19; m/z found, 438.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.37 (s, 1H), 8.80 (d, J=4.7, 1H), 8.08(d, J=9.2, 1H), 7.68-7.63 (m, 3H), 7.45-7.41 (m, 2H), 7.35 (d, J=4.7,1H), 7.29 (dd, J=7.1, 1.0, 1H), 7.14 (dd, J=7.2, 0.9, 1H), 6.87 (d,J=1.3, 1H), 6.31 (d, J=7.9, 1H), 4.64-4.61 (m, 1H), 3.91 (s, 3H), 3.24(dd, J=15.5, 5.2, 1H), 3.05 (dd, J=6.7, 6.7, 2H), 2.72 (dd, J=15.6, 8.1,1H), 2.31-2.25 (m, 1H), 2.15-2.07 (m, 1H).

Example 22

4,6-Difluoro-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₁F₂N₅O₂, 473.17; m/z found,474.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.77 (s, 1H), 8.81 (d, J=4.7,1H), 8.09 (d, J=9.2, 1H), 7.70 (s, 1H), 7.66 (d, J=2.7, 1H), 7.44 (dd,J=9.2, 2.8, 1H), 7.37 (d, J=4.7, 1H), 6.96 (d, J=8.7, 1H), 6.93 (d,J=2.0, 1H), 6.66 (dt, J=10.0, 1.9, 1H), 6.31 (d, J=8.0, 1H), 4.63-4.58(m, 1H), 3.92 (s, 3H), 3.26 (dd, J=15.5, 5.1, 1H), 3.06 (dd, J=6.6, 6.6,2H), 2.74 (dd, J=15.5, 8.1, 1H), 2.32-2.28 (m, 1H), 2.16-2.10 (m, 1H).

Example 23

Benzo[b]thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂N₄O₂S, 454.15; m/z found,455.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.08 (d,J=9.2, 1H), 7.85 (dd, J=16.8, 7.9, 1H), 7.80 (s, 2H), 7.69 (s, 1H), 7.66(dd, J=2.7, 2.7, 1H), 7.44-7.41 (m, 3H), 7.36 (d, J=4.7, 1H), 6.29 (d,J=7.7, 1H), 4.62-4.56 (m, 1H), 3.91 (s, 3H), 3.25 (dd, J=15.4, 5.1, 1H),3.04 (dd, J=6.3, 6.3, 2H), 2.73 (dd, J=15.5, 8.1, 1H), 2.31-2.27 (m,1H), 2.15-2.09 (m, 1H).

Example 24

4-Fluoro-benzo[b]thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

The reaction mixture was stirred overnight instead of 1.5 h. MS (ESI):exact mass calculated for C₂₆H₂₁FN₄O₂S, 472.14; m/z found, 473.3 [M+H]⁺.¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.08 (d, J=9.2, 1H), 7.85(s, 1H), 7.69 (s, 1H), 7.66 (d, J=2.7, 1H), 7.63 (d, J=7.6, 1H), 7.43(dd, J=9.2, 2.8, 1H), 7.41-7.37 (m, 1H), 7.36 (d, J=4.7, 1H), 7.07 (dd,J=8.1, 1.7, 1H), 6.37 (d, J=7.7, 1H), 4.61-4.56 (m, 1H), 3.91 (s, 3H),3.26 (dd, J=15.5, 5.1, 1H), 3.04 (dd, J=6.3, 6.3, 2H), 2.74 (dd, J=15.5,8.2, 1H), 2.31-2.28 (m, 1H), 2.16-2.09 (m, 1H).

Example 25

Benzofuran-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂N₄O₃, 438.17; m/z found, 439.3[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.81 (d, J=4.7, 1H), 8.09 (d, J=9.2,1H), 7.71 (s, 1H), 7.69 (d, J=7.7, 1H), 7.67 (d, J=2.7, 1H), 7.52-7.51(m, 2H), 7.45-7.42 (m 2H), 7.38 (d, J=4.7, 1H), 7.31 (dd, J=7.8, 7.8,1H), 6.76 (d, J=8.0, 1H), 4.63-4.58 (m, 1H), 3.92 (s, 3H), 3.25 (dd,J=15.5, 5.2, 1H), 3.09-3.03 (m, 2H), 2.76 (dd, J=15.5, 8.3, 1H),2.33-2.28 (m, 1H), 2.16-2.10 (m, 1H).

Example 26

2-(1H-Indol-2-yl)-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-2-oxo-acetamide

MS (ESI): exact mass calculated for C₂₇H₂₃N₅O₃, 465.18; m/z found, 466.3[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.21 (s, 1H), 9.14 (d, J=3.0, 1H), 8.81(d, J=4.7, 1H), 8.42 (d, J=7.3, 1H), 8.08 (d, J=9.2, 1H), 7.72-7.70 (m,2H), 7.65 (d, J=2.7, 1H), 7.46-7.43 (m, 2H), 7.38-7.32 (m, 3H),4.47-4.41 (m, 1H), 3.93 (s, 3H), 3.19 (dd, J=15.5, 5.1, 1H), 3.06-3.00(m, 2H), 2.74 (dd, J=15.5, 7.9, 1H), 2.28-2.22 (m, 1H), 2.14-2.08 (m,1H).

Example 27

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-amide

The crude material was purified by supercritical fluid chromatography toprovide the title compound. MS (ESI): exact mass calculated forC₂₆H₂₃N₅O₃S, 485.15; m/z found, 486.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.79 (d, J=4.7, 1H), 8.73 (br s, 1H), 8.07 (d, J=9.3, 1H), 7.67 (s, 1H),7.65 (d, J=2.8, 1H), 7.53 (s, 1H), 7.42 (dd, J=2.8, 9.3, 1H), 7.36-7.30(m, 3H), 6.33 (d, J=7.9, 1H), 4.68-4.65 (m, 1H), 3.89 (s, 3H), 3.35 (dd,J=5.3, 16.1, 1H), 3.44 (s, 2H), 2.91-2.80 (m, 3H), 2.24-2.20 (m, 1H),2.02-1.93 (m, 1H).

Example 28

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-amide

The crude material was purified by supercritical fluid chromatography toprovide the title compound. MS (ESI): exact mass calculated forC₂₆H₂₂FN₅O₃S, 503.14; m/z found, 504.8 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃):8.95 (s, 1H), 8.80 (d, J=4.7, 1H), 8.08 (d, J=9.2, 1H), 7.89 (d, J=6.8,1H), 7.69 (s, 1H), 7.67 (d, J=2.8, 1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.35(d, J=4.7, 1H), 7.11 (d, J=11.4, 1H), 6.94 (dd, J=14.7, 7.9, 1H),4.82-4.79 (m, 1H), 3.91 (s, 3H), 3.46 (s, 2H), 3.36 (dd, J=16.1, 5.3,1H), 2.96-2.92 (m, 1H), 2.91-2.83 (m, 2H), 2.26-2.23 (m, 1H), 2.04-1.97(m, 1H).

Example 29

N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-phenyl-acrylamide

MS (ESI): exact mass calculated for C₂₆H₂₄N₄O₂, 424.19; m/z found, 425.8[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.79 (d, J=4.7, 1H), 8.08 (d, J=9.2,1H), 7.70-7.66 (m, 3H), 7.52-7.49 (m, 2H), 7.43 (dd, J=9.2, 2.8, 1H),7.38-7.33 (m, 4H), 6.44 (d, J=15.6, 1H), 5.91 (d, J=7.9, 1H), 4.57-4.52(m, 1H), 3.91 (s, 3H), 3.18 (dd, J=15.6, 5.1, 1H), 3.02-2.99 (m, 2H),2.66 (dd, J=15.6, 7.6, 1H), 2.24-2.17 (m, 1H), 2.12-2.02 (m, 1H).

Example 30

N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-thiophen-2-yl-acrylamide

MS (ESI): exact mass calculated for C₂₄H₂₂N₄O₂S, 430.15; m/z found,431.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.08 (d,J=9.2, 1H), 7.80 (d, J=15.2, 1H), 7.68-7.66 (m, 2H), 7.43 (dd, J=9.2,2.8, 1H), 7.35 (d, J=4.7, 1H), 7.32 (d, J=5.1, 1H), 7.23 (d, J=3.6, 1H),7.05-7.04 (m, 1H), 6.22 (d, J=15.2, 1H), 5.72 (d, J=7.9, 1H), 4.56-4.50(m, 1H), 3.92 (s, 3H), 3.17 (dd, J=15.5, 5.2, 1H), 3.03-2.96 (m, 2H),2.67-2.62 (m, 1H), 2.23-2.17 (m, 1H), 2.09-2.03 (m, 1H).

Example 31

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-quinolin-8-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide

HPLC: R_(t)=8.00 min. MS (ESI): exact mass calculated for C₂₅H₂₁N₅O₂S,455.14; m/z found, 456.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.96 (dd,J=4.1, 1.6, 1H), 8.48 (s, 1H), 8.24 (dd, J=8.3, 1.6, 1H), 8.14 (d,J=7.5, 1H), 7.76 (d, J=8.1, 1H), 7.62 (t, J=7.8, 1H), 7.47 (dd, J=4.1,4.1, 1H), 7.38 (d, J=1.4, 1H), 7.34-7.29 (m, 2H), 6.30 (d, J=7.9, 1H),4.62-4.60 (m, 1H), 3.43 (s, 2H), 3.38 (dd, J=15.0, 5.0, 1H), 2.99-2.93(m, 2H), 2.74 (dd, J=15.0, 5.0, 1H), 2.15-2.12 (m, 2H).

Example 32

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-quinolin-8-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide

MS (ESI): exact mass calculated for C₂₅H₂₀FN₅O₂S, 473.13; m/z found474.3 [M+H]⁺. ¹H NMR: 8.96 (dd, J=3.6, 1.8, 1H), 8.51 (br s, 1H), 8.48(br s, 1H), 8.23 (dd, J=8.3, 1.8, 1H), 8.16 (dd, J=7.6, 1.4, 1H),7.75-7.76 (m, 1H), 7.74 (br s, 1H), 7.62 (t, J=7.9, 1H), 7.47 (q, J=4.2,1H), 7.08 (d, J=11.3, 1H), 6.89 (dd, J=13.3, 7.7, 1H), 4.67 (br s, 1H),3.45 (s, 2H), 3.21 (dd, J=15.5, 5.1, 1H), 2.93-3.07 (m, 2H), 2.76 (dd,J=15.4, 7.1, 1H), 2.25-2.19 (m, 1H), 2.13-2.06 (m, 1H).

Example 33

7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide

To a solution of7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (17mg, 0.076 mmol),2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (18 mg, 0.069mmol), and HOBT (24.0 mg, 0.103 mmol) in DMF (1 mL) was added EDC (20.0mg, 0.103 mmol). The reaction mixture was stirred overnight at RT. Thereaction was diluted with EtOAc (10 mL) and 1 N NaOH (5 mL). The aqueouslayer was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with 1 N HCl (10 mL), brine (10 mL), dried (MgSO₄),filtered, and concentrated. The crude was purified by acidic reversephase HPLC. The TFA salt of the title compound was diluted in CH₃OH (10mL) and treated with anionic exchange resin (550 Å, OH). The mixture wasstirred at RT for 20 min. The mixture was filtered and the filtrate wasconcentrated to afford 2.8 mg (8%) of the title compound. MS (ESI):exact mass calculated for C₂₆H₂₁FN₄O₂S, 472.14; m/z found, 473.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 8.76 (br s, 1H), 7.91-7.84 (m, 4H), 7.54-7.49(m, 5H), 7.11 (d, J=11.4, 1H), 6.97-6.92 (m, 1H), 4.73-4.71 (m, 1H),3.46 (s, 2H), 3.20 (dd, J=15.5, 5.0, 1H), 3.08-3.02 (m, 1H), 3.00-2.94(m, 1H), 2.74 (dd, J=15.5, 7.0, 1H), 2.26-2.22 (m, 1H), 2.17-2.11 (m,1H).

Example 34

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide

This compound was prepared according to the methods described forExample 33. MS (ESI): exact mass calculated for C₂₆H₂₂N₄O₂S, 454.15; m/zfound, 455.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.94-7.86 (m, 3H),7.54-7.49 (m, 6H), 7.33-7.27 (m, 2H), 6.35-6.31 (m, 1H), 4.64 (br s,1H), 3.43 (s, 2H), 3.18 (dd, J=15.7, 4.9, 1H), 3.06-2.94 (m, 2H), 2.70(dd, J=15.6, 7.1, 1H), 2.25-2.19 (m, 1H), 2.14-2.07 (m, 1H).

Example 35

6-Dimethylamino-2-fluoro-3-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-benzonitrile

To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg,0.36 mmol) in CH₃OH (7 mL) was added2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT.NaBH₄ (19 mg, 0.50 mmol) was then added and the suspension was stirredfor 30 min at RT. The reaction mixture was diluted with a few drops ofH₂O, and the solvents were removed under reduced pressure. The crudematerial was purified by basic reverse phase to provide 70 mg (44%) ofthe title compound. MS (ESI): exact mass calculated for C₂₆H₂₆FN₇O,471.22; m/z found, 472.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09 (s, 1H),8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t,J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H),4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77(m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H).

The compounds in Examples 36-43 were prepared according to the methodsdescribed for Example 35.

Example 36

(3,4-Dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₆N₆OS, 458.19; m/z found, 459.5[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.08 (s, 1H), 8.75 (d, J=5.1, 1H), 8.25(d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.18 (d, J=9.1, 1H), 6.94 (d,J=7.9, 1H), 6.60 (dd, J=7.9, 1.7, 1H), 6.50 (s, 1H), 4.10 (s, 3H), 3.99(br s, 1H), 3.76 (s, 2H), 3.62-3.61 (m, 2H), 3.04-2.96 (m, 5H),2.83-2.76 (m, 1H), 2.53 (dd, J=15.0, 8.8, 1H), 2.16-2.10 (m, 1H),1.88-1.80 (m, 1H).

Example 37

Benzo[1,3]dioxol-5-ylmethyl-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]amine

MS (ESI): exact mass calculated for C₂₄H₂₃N₅O₃, 429.18; m/z found, 430.5[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.25(d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.18 (d, J=9.1, 1H), 6.86 (d,J=1.6, 1H), 6.79 (dd, J=7.9, 1.6, 1H), 6.75 (d, J=7.9, 1H), 5.93 (s,2H), 4.10 (s, 3H), 3.82 (s, 2H), 3.08-2.96 (m, 3H), 2.83-2.77 (m, 1H),2.51 (dd, J=15.3, 8.3, 1H), 2.16-2.09 (m, 1H), 1.86-1.79 (m, 1H).

Example 38

(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₄H₂₁F₂N₅O₃, 465.16; m/z found,466.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10 (s, 1H), 8.75 (d, J=5.1,1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.18 (d, J=9.1, 1H), 7.13(d, J=1.5, 1H), 7.04 (dd, J=8.1, 1.5, 1H), 6.98 (d, J=8.1, 1H), 4.09 (s,3H), 3.89 (s, 2H), 3.06-2.96 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd,J=15.0, 8.1, 1H), 2.15-2.11 (m, 1H), 1.87-1.80 (m, 1H), 1.34 (br s, 1H).

Example 39

(4-Dimethylamino-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₈N₆O, 428.23; m/z found, 451.8[M+Na]⁺. ¹H NMR (500 MHz, CDCl₃): 9.08 (s, 1H), 8.75 (d, J=5.1, 1H),8.25 (d, J=9.1, 1H), 8.13 (d, J=5.1, 1H), 7.22 (d, J=8.7, 2H), 7.17 (d,J=9.1, 1H), 6.70 (d, J=8.7, 2H), 4.00 (s, 3H), 3.83 (s, 2H), 3.11-3.06(m, 1H), 3.06-2.96 (m, 2H), 2.91 (s, 6H), 2.82-2.75 (m, 1H), 2.57-2.53(m, 1H), 2.16-2.13 (m, 2H), 1.87-1.79 (m, 1H).

Example 40

7-Fluoro-6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one

MS (ESI): exact mass calculated for C₂₅H₂₃FN₆O₂S, 490.16; m/z found,491.7 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 9.07 (s, 1H), 8.70 (d, J=4.8,1H), 8.23 (d, J=8.6, 1H), 8.07 (d, J=4.8, 1H), 7.26 (d, J=9.2, 1H), 7.05(d, J=9.2, 1H), 6.99 (d, J=6.4, 1H), 4.10 (s, 3H), 3.88 (s, 2H), 3.38(s, 2H), 3.06-2.95 (m, 3H), 2.80-2.73 (m, 1H), 2.50 (dd, J=14.6, 8.5,1H), 2.22-2.17 (m, 1H), 1.82-1.77 (m, 1H).

Example 41

6-{[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one

DMF was used in place of CH₃OH. HPLC: R_(t)=6.16 min. MS (ESI): exactmass calculated for C₂₅H₂₄N₆O₂S, 472.17; m/z found, 473.5 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.11 (s, 1H), 8.76 (d, J=5.0, 1H), 8.26 (d, J=9.1,1H), 8.16 (d, J=5.0, 1H), 7.77 (br s, 1H), 7.27 (d, J=7.9, 1H), 7.19 (d,J=9.1, 1H), 7.02 (dd, J=7.9, 1.4, 1H), 6.86 (d, J=1.4, 1H), 4.11 (s,3H), 3.87 (s, 2H), 3.41 (s, 2H), 3.01-2.97 (m, 3H), 2.85-2.78 (m, 1H),2.56-2.51 (m, 1H), 2.17-2.13 (m, 1H), 1.88-1.82 (m, 1H).

Example 42

(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

DMF was used in place of CH₃OH. HPLC: R_(t)=6.85 min. MS (ESI): exactmass calculated for C₂₅H₂₅N₅O₃, 443.2; m/z found, 444.6 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.09 (s, 1H), 8.75 (d, J=5.0, 1H), 8.26 (d, J=9.1,1H), 8.14 (d, J=5.0, 1H), 7.18 (d, J=9.1, 1H), 6.88 (s, 1H), 6.82 (s,2H), 4.26 (s, 4H), 4.41 (s, 3H), 3.8 (s, 2H), 3.10-3.00 (m, 3H),2.83-2.77 (m, 1H), 2.56-2.51 (m, 1H), 2.17-2.13 (m, 1H), 1.88-1.80 (m,1H).

Example 43

(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

Once the reaction was complete, the reaction mixture was extracted withEtOAc (3×20 mL), washed with brine (20 mL), dried (MgSO₄), andconcentrated. The crude material was purified on SiO₂ (0-100%EtOAc/hexanes) to provide the title compound. MS (ESI): exact masscalculated for C₂₅H₂₄FN₅O₃, 461.19; m/z found, 462.4 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 9.08 (s, 1H), 8.75 (d, J=4.9, 1H), 8.25 (d, J=9.1, 1H),8.14 (d, J=5.1, 1H), 7.17 (d, J=9.0, 1H), 6.84 (d, J=7.2, 1H), 6.56 (d,J=10.5, 1H), 4.24-4.19 (m, 5H), 4.10 (s, 3H), 3.85 (s, 2H), 3.05-2.96(m, 3H), 2.83-2.76 (m, 1H), 2.53-2.49 (m, 1H), 2.14-2.11 (m, 1H),1.86-1.81 (m, 1H).

Example 44

6-{[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

To a solution of3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (153 mg,0.858 mmol) in DMF (1.36 mL) was added2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(84.4 mg, 0.286 mmol). The reaction mixture was stirred overnight at RT.NaBH₄ (37.6 mg, 0.572 mmol) was then added and the suspension wasstirred for 1 h at RT. The reaction mixture was diluted with CH₃OH andpoured into 1 N NaOH. The organic layer was separated, washed with brine(4×), dried (Na₂SO₄), filtered, and concentrated. The crude material waspurified by basic reverse phase HPLC to provide 4.6 mg (3.5%) of thetitle compound. MS (ESI): exact mass calculated for C₂₄H₂₃N₇O₃, 457.19;m/z found, 458.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09 (s, 1H), 8.75 (d,J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.19 (d, J=8.0,1H), 7.17 (d, J=9.1, 1H), 6.95 (d, J=8.0, 1H), 4.62 (s, 2H), 4.09 (s,3H), 3.92 (s, 2H), 3.09-2.98 (m, 3H), 2.83-2.77 (m, 1H), 2.56 (dd,J=14.6, 7.9, 1H), 2.17-2.14 (m, 1H), 1.89-1.82 (m, 1H), 1.24 (s, 1H).

Example 45

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-propyl)-amine

To a stirring solution of2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(50 mg, 0.17 mmol) and 3-phenylpropionaldehyde (20 mg, 0.2 mmol) indichloroethane (2 mL) was added NaB(OAc)₃H (37 mg, 0.17 mmol) and aceticacid (2 drops). The reaction mixture was stirred overnight at RT. Water(5 mL) was added, and the aqueous layer was extracted with CH₂Cl₂ (3×15mL). The combined organic layers were washed with brine (10 mL), dried(MgSO₄), filtered, and concentrated. The crude material was purified onSiO₂ (0-5% CH₃OH/CH₂Cl₂) to give 24 mg (36%) of the title compound as aclear oil. MS (ESI): exact mass calculated for C₂₅H₂₇N₅O, 413.22; m/zfound, 414.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.07 (s, 1H), 8.72-8.70(m, 1H), 8.25-8.23 (m, 1H), 8.08-8.07 (m, 1H), 7.30-7.21 (m, 5H),7.18-7.16 (m, 1H), 4.09 (s, 3H), 3.06-2.90 (m, 3H), 2.80-2.68 (m, 5H),2.46-2.40 (m, 1H), 2.19-2.16 (m, 1H), 1.93-1.86 (m, 2H), 1.77-1.67 (m,1H).

Example 46

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-allyl)-amine

To a suspension of2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(50 mg, 0.17 mmol) and trans-cinnamaldehyde (20 mg, 0.15 mmol) inTi(OiPr)₄ (0.074 mL, 0.25 mmol) was added CH₃OH (1 mL). The suspensionwas stirred for 3 h at RT. NaBH₄ was added (9.0 mg, 0.24 mmol) and thereaction mixture was stirred for another 10 min, followed by theaddition of 3 N NaOH (5 mL). The aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (10 mL),dried (MgSO₄), filtered, and concentrated. The crude was purified onSiO₂ (0-5% CH₃OH/CH₂Cl₂) to give 30 mg (50%) of the title compound as aclear oil. MS (ESI): exact mass calculated for C₂₅H₂₅N₅O, 411.21; m/zfound, 412.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10 (s, 1H), 8.76 (d,J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.15 (d, J=5.1, 2H), 7.37 (d, J=7.4,2H), 7.30 (d, J=7.4, 2H), 7.23-7.20 (m, 1H), 7.18 (d, J=9.1, 1H), 6.57(d, J=15.9, 1H), 6.34 (dt, J=15.9, 6.4, 1H), 4.10 (s, 3H), 3.55 (d,J=6.4, 2H), 3.15-3.11 (m, 1H), 3.06-3.01 (m, 1H), 2.99 (t, J=5.3, 1H),2.86-2.80 (m, 1H), 2.53 (q, J=8.5, 1H), 2.17-2.15 (m, 1H), 1.88-1.81 (m,1H).

Example 47

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-pyridin-3-yl-allyl)-amine

This compound was prepared according to the methods described forExample 35. MS (ESI): exact mass calculated for C₂₄H₂₄N₆O, 412.20; m/zfound, 413.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.07 (s, 1H), 8.72 (d,J=5.0, 1H), 8.55 (d, J=2.0, 1H), 8.42-8.41 (m, 1H), 8.22 (d, J=9.0, 1H),8.11 (d, J=5.0, 1H), 7.66 (d, J=8.0, 1H), 7.25-7.16 (m, 1H), 7.14 (d,J=9.0, 1H), 6.53 (d, J=15.0, 1H), 6.40-6.37 (m, 1H), 4.06 (s, 3H), 3.55(d, J=5.0, 2H), 3.10-3.08 (m, 1H), 3.03-2.96 (m, 2H), 2.82-2.80 (m, 1H),2.53-2.48 (m, 1H), 2.13-2.12 (m, 1H), 1.82-1.81 (m, 1H).

Example 48

[3-(3,4-Dichloro-phenyl)-propyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]amine

A.3-(3,4-Dichloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-propionamide.To a solution of 3-(3,4-dichloro-phenyl)propionic acid (30 mg, 0.1 mmol)in DMF (1 mL) was added HOBT (28 mg, 0.21 mmol), EDC (40 mg, 0.2 mmol),and a solution of2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(50 mg, 0.2 mmol) in DMF (1 mL). The reaction mixture was stirredovernight at RT. Water was added (10 mL), and the aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (15 mL), dried (MgSO₄), filtered, and concentrated. The crudewas purified on SiO₂ (0-5% CH₃OH/CH₂Cl₂), to give a yellow oil. The oilwas then washed with 1 N NaOH (3×10 mL), brine (10 mL), dried (MgSO₄),and filtered to provide 50 mg (72%) of a white solid. MS (ESI): exactmass calculated for C₂₅H₂₃Cl₂N₅O₂, 495.12; m/z found, 496.4 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 9.13 (s, 1H), 8.78 (d, J=5.1, 1H), 8.27 (d, J=9.1,1H), 8.16 (d, J=5.1, 1H), 7.34 (d, J=8.2, 1H), 7.31 (d, J=2.0, 1H), 7.20(d, J=9.1, 1H), 7.05 (dd, J=8.2, 2.0, 1H), 5.43 (d, J=7.5, 1H),4.40-4.34 (m, 1H), 4.10 (s, 3H), 3.05 (dd, J=15.6, 5.1, 1H), 2.97-2.80(m, 4H), 2.51-2.41 (m, 3H), 2.07-2.01 (m, 1H), 1.96-1.88 (m, 1H).

B.[3-(3,4-Dichloro-phenyl)-propyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine.A solution of3-(3,4-dichloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-propionamide(20 mg, 0.04 mmol) in CH₂Cl₂ (2 mL) was treated with DIBAL-H (1 Msolution in THF, 0.4 mL, 0.4 mmol) at −78° C. for 30 min. The reactionmixture was warmed to 0° C. and stirred for 20 min, then was stirred atRT for 3 h. The solution was re-cooled (−78° C.), and treated withadditional DIBAL-H (0.4 mL, 0.4 mmol). The solution was stirred at −78°C. for 30 min, followed by 20 min at 0° C. Satd. potassium sodiumtartrate solution (5 mL) was added to the reaction mixture at −30° C.The reaction mixture was warmed to RT and stirred for 2 h. Water (10 mL)was added, and the aqueous layer was extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (15 mL), dried (MgSO₄),filtered, and concentrated. The crude was purified on SiO₂ (0-5%CH₃OH/CH₂Cl₂) to give 10 mg (50%) of the title compound as a clear oil.MS (ESI): exact mass calculated for C₂₅H₂₅Cl₂N₅O, 481.14; m/z found,482.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.11 (s, 1H), 8.77 (d, J=5.1,1H), 8.26 (d, J=9.1, 1H), 8.16 (d, J=5.1, 1H), 7.34 (d, J=8.2, 1H), 7.30(d, J=2.0, 1H), 7.19 (d, J=9.1, 1H), 7.03 (dd, J=8.2, 2.0, 1H), 4.10 (s,3H), 3.04-2.95 (m, 3H), 2.85-2.74 (m, 3H), 2.68-2.65 (m, 2H), 2.52-2.48(m, 1H), 2.14-2.11 (m, 1H), 1.87-1.78 (m, 4H).

Example 49

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-p-tolyl-propyl)-amine

A.N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-p-tolyl-propionamide.This compound was prepared according to the methods described in Example48, step A. MS (ESI): exact mass calculated for C₂₆H₂₇N₅O₂, 441.22; m/zfound, 442.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.10 (s, 1H), 8.77 (d,J=5.1, 1H), 8.27 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.20 (d, J=9.1,1H), 7.09 (s, 4H), 5.44 (d, J=7.9, 1H), 4.39-4.31 (m, 1H), 4.09 (s, 3H),3.04 (dd, J=15.6, 5.1, 1H), 2.96-2.86 (m, 3H), 2.83-2.77 (m, 1H),2.51-2.45 (m, 3H), 2.32-2.29 (m, 3H), 2.04-2.00 (m, 1H), 1.93-1.86 (m,1H).

B.[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-o-tolyl-propyl)-amine.A solution ofN-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-p-tolyl-propionamide(0.020 g, 0.045 mmol) in CH₂Cl₂ (2 mL) was treated with DIBAL-H (1 Msolution in THF, 0.45 mL, 0.45 mmol) at −78° C. for 30 min. The reactionmixture was warmed to 0° C. and stirred for 20 min, then at RT for 1 h.Satd. potassium sodium tartrate solution (5 mL) was added at −30° C. Thesolution was warmed to RT and stirred for 1 h. Water (10 mL) was added,and the aqueous layer was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (15 mL), dried (MgSO₄), filtered,and concentrated. The crude was purified on SiO₂ (0-5% CH₃OH/CH₂Cl₂) togive 10 mg (53%) of the title compound as a clear oil. MS (ESI): exactmass calculated for C₂₆H₂₉N₅O, 427.24; m/z found, 428.5 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 9.10 (s, 1H), 8.77 (d, J=5.1, 1H), 8.26 (d, J=9.1,1H), 8.15 (d, J=5.1, 1H), 7.19 (d, J=9.1, 1H), 7.09 (s, 4H), 4.10 (s,3H), 3.03-2.95 (m, 3H), 2.84-2.76 (m, 3H), 2.68-2.64 (m, 2H), 2.54-2.50(m, 1H), 2.31 (s, 3H), 2.15-2.13 (m, 1H), 1.91-1.80 (m, 4H).

Example 50

(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

This compound was prepared according to the methods described in Example35, using DMF instead of CH₃OH. HPLC: R_(t)=6.45 min. MS (ESI): exactmass calculated for C₂₆H₂₆N₄O₃, 442.5; m/z found, 443.4 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 8.78 (d, J=4.7, 1H), 8.06 (d, J=9.2, 1H), 7.69 (d,J=2.8, 1H), 7.63 (s, 1H), 7.40 (dd, J=9.2, 2.8, 1H), 7.32 (d, J=4.7,1H), 6.88 (s, 1H), 6.83 (s, 1H), 4.27 (s, 4H), 3.92, (s, 3H), 3.79 (s,2H), 3.11-2.78 (m, 3H), 2.85-2.78 (m, 1H), 2.54-2.49 (m, 1H), 2.17-2.13(m, 1H), 1.88-1.83 (m, 2H).

Example 51

(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

This compound was prepared according to the methods described forExample 43. MS (ESI): exact mass calculated for C₂₆H₂₅FN₄O₃, 460.19; m/zfound, 461.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.77 (d, J=4.7, 1H), 8.05(d, J=9.2, 1H), 7.69 (d, J=2.8, 1H), 7.63 (s, 1H), 7.41 (dd, J=7.0, 2.8,1H), 7.32 (d, J=4.7, 1H), 6.84 (d, J=7.2, 1H), 6.60 (d, J=10.4, 1H),4.24-4.20 (m, 4H), 3.90 (s, 3H), 3.86 (s, 2H), 3.07-2.97 (m, 3H),2.84-2.78 (m, 1H), 2.52 (dd, J=15.1, 8.2, 1H), 2.15-2.12 (m, 1H),1.86-1.81 (m, 1H).

Example 52

6-{[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one

This compound was prepared according to the methods described in Example35, using DMF instead of CH₃OH. HPLC: R_(t)=5.86 min. MS (ESI): exactmass calculated for C₂₆H₂₅N₅O₂S, 471.17; m/z found, 472.4 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.78 (d, J=4.7, 1H), 8.06 (d, J=9.2, 1H), 7.80 (br s,1H), 7.69 (d, J=2.7, 1H), 7.64 (s, 1H), 7.42 (dd, J=9.2, 2.7, 1H), 7.32(d, J=4.7, 1H), 7.27 (d, J=7.9, 1H), 7.02 (dd, J=7.9, 1.5, 1H), 6.88 (d,J=1.4, 1H), 3.92-3.81 (m, 5H), 3.42 (s, 2H), 3.11-2.98 (m, 3H),2.86-2.80 (m, 1H), 2.55-2.50 (m, 1H), 2.18-2.15 (m, 1H), 1.89-1.81 (m,1H).

Example 53

7-Fluoro-6-{[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one

This compound was prepared according to the methods described in Example35, using DMF instead of CH₃OH. MS (ESI): exact mass calculated forC₂₆H₂₄FN₅O₂S, 489.16; m/z found, 490.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.78 (d, J=4.7, 1H), 8.09-8.06 (m, 2H), 7.69 (d, J=2.8, 1H), 7.65 (s,1H), 7.42 (dd, J=9.2, 2.8, 1H), 7.33 (d, J=4.7, 1H), 7.05 (d, J=9.3,1H), 6.92 (d, J=6.3, 1H), 3.93 (s, 2H), 3.91 (s, 3H), 3.42 (s, 2H),3.05-3.00 (m, 3H), 2.88-2.80 (m, 1H), 2.54 (dd, J=14.4, 7.6, 1H),2.19-2.16 (m, 1H), 1.91-1.82 (m, 1H).

Example 54

6-{[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

This compound was prepared according to the methods described forExample 44. MS (ESI): exact mass calculated for C₂₅H₂₄N₆O₃, 456.19; m/zfound, 457.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.77 (d, J=4.7, 1H), 8.06(d, J=9.2, 1H), 7.69 (d, J=2.8, 1H), 7.63 (s, 1H), 7.41 (dd, J=9.2, 2.8,1H), 7.31 (d, J=4.7, 1H), 7.21 (d, J=8.0, 1H), 6.96 (d, J=8.1, 1H), 4.63(s, 2H), 3.93 (s, 2H), 3.89 (s, 3H), 3.05-3.00 (m, 3H), 2.85-2.80 (m,1H), 2.56 (dd, J=15.0, 8.3, 1H), 2.58-2.54 (m, 1H), 1.89-1.83 (m, 1H),1.66 (br s, 1H).

Example 55

[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-phenyl-allyl)-amine

To a solution of trans-cinnamaldehyde (0.0275 mL, 0.218 mmol) in DMF(0.74 mL) was added2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(45.7 mg, 0.155 mmol). The reaction mixture was stirred overnight at RT.NaBH₄ (11.7 mg, 0.31 mmol) was then added and the suspension was stirredfor 30 min at RT. The reaction mixture was diluted with CH₃OH andpurified directly by acidic reverse phase HPLC to provide 23.8 mg of theTFA salt of the title compound. To this salt in CH₃OH was added anionicexchange resin (550 Å, OH). The mixture was stirred at RT for 20 min.The mixture was filtered and the filtrate was concentrated to afford13.6 mg (21%) of the title compound. MS (ESI): exact mass calculated forC₂₆H₂₆N₄O, 410.21; m/z found, 411.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.78 (d, J=4.7, 1H), 8.06 (d, J=9.2, 1H), 7.70 (d, J=2.8, 1H), 7.65 (s,1H), 7.43-7.20 (m, 8H), 6.58 (d, J=15.9, 1H), 6.36 (dt, J=15.9, 6.4,1H), 3.90 (s, 3H), 3.57 (d, J=6.1, 2H), 3.19-3.12 (m, 1H), 3.07-2.99 (m,2H), 2.89-2.81 (m, 1H), 2.53 (dd, J=15.3, 8.5, 1H), 2.20-2.17 (m, 1H),1.90-1.81 (m, 1H).

Example 56

[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-methyl-3-phenyl-allyl)-amine

This compound was prepared according to the methods described in Example35. MS (ESI): exact mass calculated for C₂₇H₂₈N₄O, 424.23; m/z found,425.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.78 (d, J=4.7, 1H), 8.06 (d,J=9.2, 1H), 7.71 (d, J=2.7, 1H), 7.65 (s, 1H), 7.42 (dd, J=9.2, 2.8,1H), 7.36-7.26 (m, 5H), 7.23-7.20 (m, 1H), 6.51 (s, 1H), 3.90 (s, 3H),3.48 (s, 2H), 3.13-2.99 (m, 3H), 2.89-2.85 (m, 1H), 2.54 (dd, J=15.0,8.3, 1H), 2.20-2.17 (m, 1H), 1.95 (s, 3H), 1.88-1.84 (m, 1H), 1.28-1.25(m, 1H).

Example 57

[3-(4-Fluoro-phenyl)-allyl]-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

This compound was prepared according methods described for Example 35.MS (ESI): exact mass calculated for C₂₆H₂₅FN₄O, 428.20; m/z found, 429.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.76 (d, J=4.7, 1H), 8.05 (d, J=9.2,1H), 7.68 (d, J=2.8, 1H), 7.64 (s, 1H), 7.40 (dd, J=9.2, 2.8, 1H),7.35-7.30 (m, 3H), 7.04-6.96 (m, 2H), 6.53 (d, J=15.9, 1H), 6.28-6.23(m, 1H), 3.89 (s, 3H), 3.54 (d, J=6.4, 2H), 3.46 (s, 1H), 3.14-3.11 (m,1H), 3.05-2.97 (m, 2H), 2.87-2.82 (m, 1H), 2.52 (dd, J=15.3, 8.5, 1H),2.18-2.15 (m, 1H), 1.86-1.81 (m, 1H).

Example 58

N-(3,5-Difluoro-phenyl)-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide

A. 2-Chloro-N-(3,5-difluoro-phenyl)-acetamide. To a solution of3,5-difluoroaniline (390 mg, 3.0 mmol) in CH₂Cl₂ (30 mL) at 0° C., wasadded diisopropylethylamine (0.63 mL, 3.6 mmol) followed by chloroacetylchloride (0.263 mL, 3.3 mmol), and the mixture was allowed to warm up toRT over 3 h. The mixture was quenched with satd. aq. NaHCO₃ (10 mL), andthe aqueous layer was extracted with CH₂Cl₂ (3×25 mL), washed with brine(25 mL), dried (MgSO₄), and concentrated. The resulting residue waspurified on SiO₂ (20-60% EtOAc/hexanes) to provide 600 mg (97%) of thetitle compound as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃): 8.27 (brs, 1H), 7.20-7.15 (m, 2H), 6.64-6.59 (m, 1H), 4.18 (s, 2H).

B. To a solution of2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(30 mg, 0.1 mmol) in DMF (1 mL) were added K₂CO₃ (40 mg, 0.3 mmol) and2-chloro-N-(3,5-difluoro-phenyl)-acetamide (20 mg, 0.1 mmol), and themixture was stirred for 15 h. A catalytic amount of NaI was added andthe mixture heated at 50° C. for 15 h. The mixture was diluted withEtOAc (25 mL), washed with brine (4×10 mL), dried (MgSO₄) andconcentrated. The resulting residue was purified on SiO₂ (0-5%CH₃OH/CH₂Cl₂) to provide 30 mg (64%) of the title compound as a paleyellow solid. MS (ESI): exact mass calculated for C₂₄H₂₂F₂N₆O₂, 464.18;m/z found, 465.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.30 (br s, 1H), 9.08(s, 1H), 8.76 (d, J=9.2, 1H), 8.24 (d, J=5.9, 1H), 8.19 (d, J=5.1, 1H),7.15 (d, J=9.1, 1H), 6.93-6.87 (m, 2H), 6.26 (tt, J=8.9, 2.3, 1H), 3.89(s, 3H), 3.59 (d, J=17.7, 1H), 3.36 (d, J=17.7, 1H), 3.26-3.23 (m, 1H),3.08-3.02 (m, 1H), 2.93-2.85 (m, 2H), 2.62 (dd, J=15.7, 5.7, 1H),2.12-2.08 (m, 1H), 2.00-1.96 (m, 1H).

The compounds in Examples 59-62 were prepared according to the methodsdescribed in Example 58.

Example 59

2-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-phenyl-acetamide

MS (ESI): exact mass calculated for C₂₄H₂₄N₆O₂, 428.20; m/z found, 429.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.19 (br s, 1H), 9.06 (s, 1H), 8.78 (d,J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.19 (d, J=5.1, 1H), 7.35 (d, J=5.6,2H), 7.14 (d, J=9.1, 1H), 7.05 (t, J=5.6, 2H), 6.86 (t, J=8.5, 1H), 3.91(s, 3H), 3.59 (d, J=17.5, 1H), 3.36 (d, J=17.5, 1H), 3.22-3.20 (m, 1H),3.08-3.04 (m, 1H), 2.93-2.86 (m, 2H), 2.62 (dd, J=15.6, 6.3, 1H),2.14-2.08 (m, 1H), 1.99-1.93 (m, 1H).

Example 60

2-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-p-tolyl-acetamide

MS (ESI): exact mass calculated for C₂₅H₂₆N₆O₂, 442.21; m/z found, 443.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10 (s, 1H), 9.06 (s, 1H), 8.78 (d,J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.19 (d, J=5.1, 1H), 7.22 (d, J=8.4,2H), 7.14 (d, J=9.1, 1H), 6.81 (d, J=8.3, 2H), 3.89 (s, 3H), 3.58 (d,J=17.4, 1H), 3.36 (d, J=17.4, 1H), 3.24-3.20 (m, 1H), 3.09-3.03 (m, 1H),2.92-2.86 (m, 2H), 2.62 (dd, J=15.7, 6.2, 1H), 2.15-2.10 (m, 4H),2.00-1.93 (m, 1H).

Example 61

N-(3,5-Difluoro-phenyl)-2-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide

The crude material was purified by basic reverse phase HPLC to provide30 mg (31%) of the title compound as a white solid. MS (ESI): exact masscalculated for C₂₅H₂₃F₂N₅O₂, 463.18; m/z found, 464.8 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 9.44 (br s, 1H), 8.78 (d, J=4.8, 1H), 8.08 (d, J=9.2,1H), 7.66 (d, J=2.7, 1H), 7.64 (s, 1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.27(s, 1H), 7.10-7.07 (m, 2H), 6.51 (tt, J=8.9, 2.3, 1H), 3.89 (s, 3H),3.59 (d, J=17.6, 1H), 3.46 (d, J=17.6, 1H), 3.21-2.92 (m, 4H), 2.61 (dd,J=15.6, 7.0, 1H), 2.17-2.15 (m, 1H), 1.95-1.86 (m, 1H).

Example 62

N-(3,4-Dichloro-phenyl)-2-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide

MS (ESI): exact mass calculated for C₂₅H₂₃Cl₂N₅O₂, 495.12; m/z found,496.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.77 (d, J=4.7, 1H), 8.08 (d,J=9.2, 1H), 7.74 (t, J=2.6, 1H), 7.67 (d, J=2.8, 1H), 7.62 (s, 1H), 7.43(dd, J=9.2, 2.8, 1H), 7.24 (s, 2H), 7.20 (d, J=4.7, 1H), 3.89 (s, 3H),3.59 (d, J=17.5, 1H), 3.45 (d, J=17.5, 1H), 3.22-3.21 (m, 1H), 3.08-3.04(m, 1H), 2.97-2.90 (m, 2H), 2.62 (dd, J=15.6, 6.84, 1H), 2.17-2.15 (m,1H), 1.97-1.95 (m, 1H).

Example 63

6-{2-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetyl}-4H-benzo[1,4]oxazin-3-one

To a solution of2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50mg, 0.2 mmol) in DMF (0.5 mL) was added6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (0.05 g, 0.22 mmol) andEt₃N (0.033 mL, 0.22 mmol). The reaction was heated to 50° C. andstirred for 12 h. The crude was purified directly by basic reverse phaseHPLC to afford 0.8 mg (10%) of the title compound. HPLC: R_(t)=5.50 min.MS (ESI): exact mass calculated for C₂₇H₂₅N₅O₄, 483.19; m/z found, 484.5[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.78 (d, J=4.7, 1H), 8.06 (d, J=9.1,1H), 7.69-7.61 (m, 3H), 7.42 (d, J=2.6, 1H), 7.40 (dd, J=9.1, 2.6, 1H),7.32 (d, J=4.7, 1H), 7.04 (d, J=8.9, 1H), 4.70 (s, 2H), 4.21 (s, 1H),3.89 (s, 3H), 3.11-2.80 (m, 5H), 2.62-2.58 (m, 1H), 2.26-2.17 (m, 1H),1.93-1.86 (m, 1H).

Example 64

6-{2-[2-(6-Methoxy-quinolin-4-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-acetyl}-4H-benzo[1,4]oxazin-3-one

This compound was prepared according to the methods described forExample 63. HPLC: R_(t)=5.49 min. MS (ESI): exact mass calculated forC₂₆H₂₃N₅O₄, 469.18; m/z found, 470.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.93-8.89 (m, 1H), 8.21-8.19 (m, 1H), 7.95 (s, 1H), 7.59-7.32 (m, 5H),7.03-7.01 (m, 1H), 4.90 (s, 1H), 4.66-4.63 (m, 4H), 3.94 (s, 2H),3.93-3.79 (m, 2H), 3.72-3.68 (m, 2H), 3.37-3.34 (m, 2H).

Example 65

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-amine

A.[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-carbamicacid tert-butyl ester. To a solution of[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamicacid tert-butyl ester (104 mg, 0.260 mmol) in DMF (2.6 mL) was added NaH(60% in mineral oil, 27 mg, 0.66 mmol) at 0° C. The reaction mixture waswarmed to RT and stirred for 30 min. Upon cooling the reaction mixtureto 0° C., β-bromophenetole (78 mg, 0.39 mmol) was added. The mixture waswarmed to RT, and treated with additional NaH (31 mg, 1.3 mmol) andβ-bromophenetole (261 mg, 1.30 mmol). After 30 h, H₂O (30 mL) and EtOAc(40 mL) were added to the reaction mixture. The organic layer wasseparated, washed with brine (20 mL), dried (MgSO₄), filtered, andconcentrated. The crude was purified on SiO₂ (0-100% EtOAc/hexanes) togive 65 mg (48%) of the title compound as a white solid. MS (ESI): exactmass calculated for C₂₉H₃₃N₅O₄, 515.25; m/z found, 516.4 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.09 (br s, 1H), 8.77 (d, J=5.0, 1H), 8.26 (d, J=9.1,1H), 8.15 (d, J=5.0, 1H), 7.30-7.27 (m, 2H), 7.18 (d, J=9.1, 1H),6.97-6.92 (m, 1H), 6.90 (d, J=7.8, 2H), 4.16-4.04 (m, 6H), 3.65-3.59 (m,2H), 3.09-3.05 (m, 1H), 2.92 (br s, 3H), 2.11 (br s, 2H), 1.49 (s, 9H).

B.[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-amine.To a solution of[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-carbamicacid tert-butyl ester (60 mg, 0.1 mmol) in CH₂Cl₂ (4 mL) was added TFA(1 mL). After stirring at RT for 1 h, the reaction mixture wasconcentrated. To the residue was added CH₃OH (5 mL) and anionic exchangeresin (550 Å OH, 50 mg). The mixture was stirred at RT for 2 h. Themixture was filtered and the filtrate was concentrated to afford 46 mg(96%) of the title compound as a tan solid. MS (ESI): exact masscalculated for C₂₄H₂₅N₅O₂, 415.20; m/z found, 416.4 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 9.11 (s, 1H), 8.76 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H),8.15 (d, J=5.1, 1H), 7.30-7.26 (m, 2H), 7.18 (d, J=9.1, 1H), 6.96-6.91(m, 3H), 4.16-4.10 (m, 5H), 3.74-3.69 (m, 1H), 3.16-3.06 (m, 3H),3.05-2.98 (m, 2H), 2.86-2.79 (m, 1H), 2.51 (d, J=8.5, 1H), 2.17-2.15 (m,1H), 1.87-1.79 (m, 1H).

Example 66

6-({Benzyl-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amino}-methyl)-4H-benzo[1,4]thiazin-3-one

To a mixture of6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one(30 mg, 0.06 mmol) and 4 Å molecular sieves (30 mg) was addeddichloroethane (0.4 mL) and benzaldehyde (13 μL, 0.13 mmol). Thesolution was stirred for 1 h, after which NaB(OAc)₃H (27 mg, 0.13 mmol)was added. After stirring overnight at RT, the reaction mixture washeated at 60° C. for 7 h. DMF (0.5 mL), NaBH₄ (30 mg, 0.8 mmol) andCH₂Cl₂ (0.2 mL) were then added, and the reaction mixture was heated at60° C. overnight. The mixture was diluted with satd. aq. NaHCO₃ (10 mL)and extracted with EtOAc (3×10 mL). The combined organic layers weredried (Na₂SO₄), filtered, and concentrated. The crude was purifieddirectly by basic reverse phase HPLC to afford 2 mg (5%) of the titlecompound. MS (ESI): exact mass calculated for C₃₂H₃₀N₆O₂S, 562.22; m/zfound, 563.5 [M+H]⁺.

Example 67

[[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-aceticacid tert-butyl ester

To a solution of6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one(50 mg, 0.1 mmol) in DMF (600 μL) was added Et₃N (19 μL, 0.13 mmol) andtert-butyl bromoacetate (19 μL, 0.13 mmol). The reaction mixture washeated at 50° C. overnight. The crude was purified directly by basicreverse phase HPLC to afford 15 mg (24%) of the title compound. MS(ESI): exact mass calculated for C₃₁H₃₄N₆O₄S, 586.24; m/z found, 587.23[M+H]⁺.

Example 68

[[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-aceticacid

A solution of[[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-aceticacid tert-butyl ester (5 mg, 0.009 mmol) in 4 M HCl in Et₂O (1 mL) wasstirred at RT for 3 h. The reaction mixture was concentrated to provide4.5 mg (100%) of the title compound. MS (ESI): exact mass calculated forC₂₇H₂₆N₆O₄S, 530.17; m/z found, 531.08 [M+H]⁺.

Examples 69-97 were prepared as described in the preceding examples.

Example 69

4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₄N₆O₃S, 500.16; m/z found,501.3 [M+H]⁺.

Example 70

Quinoxaline-2-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₁N₇O₂, 451.18; m/z found, 452.5[M+H]⁺.

Example 71

1H-Benzoimidazole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₂N₆O₂, 438.18; m/z found, 439.4[M+H]⁺.

Example 72

5-Bromo-thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₂H₁₉BrN₄O₂S, 482.04; m/z found,483.2 [M+H]⁺.

Example 73

5-Acetyl-thiophene-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₄H₂₂N₄O₃S, 446.14; m/z found,447.3 [M+H]⁺.

Example 74

5,6-Difluoro-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₁F₂N₅O₂, 473.17; m/z found,474.3 [M+H]⁺.

Example 75

5-Methyl-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₂₅N₅O₂, 451.20; m/z found, 452.4[M+H]⁺.

Example 76

5-Bromo-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂BrN₅O₂, 515.10; m/z found,518.2 [M+H]⁺.

Example 77

5-Chloro-1H-indole-2-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂ClN₅O₂, 471.15; m/z found,472.3 [M+H]⁺.

Example 78

2-Chloro-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-nicotinamide

MS (ESI): exact mass calculated for C₂₃H₂₀ClN₅O₂, 433.13; m/z found,434.3 [M+H]⁺.

Example 79

4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₂₇N₅O₃, 469.21; m/z found, 470.4[M+H]⁺.

Example 80

1-(4-Chloro-phenyl)-cyclopentanecarboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₉H₂₉ClN₄O₂, 500.20; m/z found,501.4 [M+H]⁺.

Example 81

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(7-chloro-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₀ClN₅O₂S, 489.10; m/z found,490.30 [M+H]⁺.

Example 82

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-fluoro-2-methyl-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂FN₅O₂S, 487.15; m/z found,488.3 [M+H]⁺.

Example 83

2-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-acetamide

MS (ESI): exact mass calculated for C₂₆H₂₅N₇O₃S, 515.17; m/z found,516.3 [M+H]⁺.

Example 84

N-Benzyl-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide

MS (ESI): exact mass calculated for C₂₅H₂₅N₆O₂, 442.21; m/z found, 443.4[M+H]⁺.

Example 85

(4-Diethylamino-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₇H₃₂N₆O, 456.26; m/z found, 455.4[M-2+H]⁺.

Example 86

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(4-piperidin-1-yl-benzyl)-amine

MS (ESI): exact mass calculated for C₂₈H₃₂N₆O, 468.26; m/z found, 467.4[M-2+H]⁺.

Example 87

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(4-pyrrolidin-1-yl-benzyl)-amine

MS (ESI): exact mass calculated for C₂₇H₃₀N₆O, 454.25; m/z found, 453.4[M-2+H]⁺.

Example 88

(2-Fluoro-4,5-dimethoxy-benzyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₆FN₅O₃, 463.20; m/z found,464.4 [M+H]⁺.

Example 89

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-[3-(2-nitro-phenyl)-allyl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₄N₆O₃, 456.19; m/z found, 457.4[M+H]⁺.

Example 90

3-(4-Chloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₅H₂₂ClN₅O₂, 459.15; m/z found,460.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃/CD₃OD): 9.11 (s, 1H), 8.74 (d,J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.12 (d, J=5.1, 1H), 7.56 (d, J=15.6,1H), 7.51-7.46 (m, 2H), 7.39-7.34 (m, 2H), 7.26 (d, J=9.1, 1H), 6.55 (d,J=15.5, 1H), 4.40-4.38 (m, 1H), 4.11 (s, 3H), 3.16 (dd, J=15.3, 5.1,1H), 3.04-2.96 (m, 2H), 2.66 (dd, J=15.4, 8.6, 1H), 2.22-2.20 (m, 1H),2.02-1.99 (m, 1H).

Example 91

3-(5-Fluoro-2-trifluoromethyl-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₆H₂₁F₄N₅O₂, 511.16; m/z found,512.3 [M+H]⁺.

Example 92

3-(3,4-Dichloro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₅H₂₁Cl₂N₅O₂, 493.11; m/z found,494.3 [M+H]⁺.

Example 93

3-(3,4-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₅H₂₁F₂N₅O₂, 461.17; m/z found,462.3 [M+H]⁺.

Example 94

3-(2-Chloro-5-nitro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₅H₂₁ClN₆O₄, 504.13; m/z found,505.3 [M+H]⁺.

Example 95

N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-pyridin-2-yl-acrylamide

MS (ESI): exact mass calculated for C₂₄H₂₂N₆O₂, 426.18; m/z found, 427.3[M+H]⁺.

Example 96

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(2,8-bis-trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₁₉F₆N₅O₂S, 591.12; m/z found,592.3 [M+H]⁺.

Example 97

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(2-trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₀F₃N₅O₂S, 523.13; m/z found,524.80 [M+H]⁺.

Example 98

7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

This compound was prepared according to methods described for Example 1.Once the reaction was complete, the reaction mixture was diluted withEtOAc (20 mL) and washed with satd. NaHCO₃ (10 mL), H₂O (4×20 mL), andbrine (10 mL), dried (Na₂SO₄), and concentrated. The crude residue wasdiluted with CH₃OH and purified by basic reverse phase HPLC. MS (ESI):exact mass calculated for C₂₆H₂₂BrN₅O₃S, 563.06; m/z found, 564.0[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.85 (d, J=4.6, 1H), 8.71 (s, 1H), 8.09(d, J=9.2, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.43 (dd, J=9.2, 2.7, 1H),7.37 (s, 1H), 7.29 (d, J=4.6, 1H), 7.06 (d, J=2.7, 1H), 6.47 (d, J=7.9,1H), 4.67-4.62 (m, 1H), 3.84 (s, 3H), 3.43 (s, 2H), 3.16 (dd, J=15.4,5.0, 1H), 2.80-2.71 (m, 2H), 2.68-2.62 (m, 1H), 2.19-2.13 (m, 1H),2.12-2.06 (m, 1H).

Example 99

3-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid[1-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

This compound was prepared according to methods described for Example 1.MS (ESI): exact mass calculated for C₂₇H₂₂F₃N₅O₃S, 553.14; m/z found,554.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.85 (d, J=4.6, 1H), 8.38 (s,1H), 8.09 (d, J=9.2, 1H), 7.65 (s, 2H), 7.43 (dd, J=9.2, 2.8, 1H), 7.09(s, 1H), 7.04 (d, J=2.8, 1H), 5.93 (d, J=8.1, 1H), 4.59-4.54 (m, 1H),3.83 (s, 3H), 3.47 (s, 2H), 3.15 (dd, J=15.2, 5.1, 1H), 2.77-2.72 (m,1H), 2.67-2.60 (m, 2H), 2.18-2.14 (m, 1H), 1.99-1.94 (m, 1H).

The compounds in Examples 100-107 were prepared according to the methodsdescribed for Example 35.

Example 100

(8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₆H₂₅FN₄O₃, 460.51; m/z found,461.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.78 (d, J=4.7, 1H), 8.06 (d,J=9.2, 1H), 7.69 (d, J=2.8, 1H), 7.63 (br s, 1H), 7.41 (dd, J=9.2, 2.8,1H), 7.33 (d, J=4.7, 1H), 6.72 (dd, J=11.1, 2.0, 1H), 6.68 (br s, 1H),4.31-4.27 (m, 4H), 3.90 (s, 3H), 3.81 (s, 2H), 3.08-2.97 (m, 3H),2.85-2.79 (m, 1H), 2.51 (dd, J=15.2, 8.4, 1H), 2.16-2.13 (m, 1H),1.85-1.82 (m, 1H).

Example 101

(8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₄FN₅O₃, 461.50; m/z found,462.1 [M+H]⁺, 484.1 [M+Na]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09 (br s, 1H),8.76 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.18 (d,J=9.1, 1H), 6.71 (dd, J=11.1, 1.9, 1H), 6.67 (br s, 1H), 4.30-4.26 (m,4H), 4.11 (s, 3H), 3.79 (s, 2H), 3.07-2.96 (m, 3H), 2.83-2.77 (m, 1H),2.51 (dd, J=14.9, 8.1, 1H), 2.15-2.11 (m, 1H), 1.86-1.78 (m, 1H).

Example 102

3,4-Dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₆H₂₇N₅OS, 457.59; m/z found, 458.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.74 (d, J=4.8, 1H), 8.01 (d, J=9.2,1H), 7.93 (s, 1H), 7.69 (d, J=2.7, 1H), 7.50-7.48 (m, 2H), 6.85 (d,J=7.8, 1H), 6.58 (dd, J=7.8, 1.7, 1H), 6.54 (d, J=1.7, 1H), 3.89 (s,3H), 3.73 (s, 2H), 3.56-3.54 (m, 2H), 3.08-2.94 (m, 5H), 2.78 (ddd,J=16.7, 11.0, 5.7, 1H), 2.50 (dd, J=14.4, 8.5, 1H), 2.23-2.20 (m, 1H),1.83-1.75 (m, 1H).

Example 103

(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₆H₂₅ClN₄O₃, 476.97; m/z found,477.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.77 (d, J=4.7, 1H), 8.05 (d,J=9.2, 1H), 7.69 (d, J=2.8, 1H), 7.63 (s, 1H), 7.40 (dd, J=9.2, 2.8,1H), 7.32 (d, J=4.7, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 4.23 (s, 4H),3.91-3.89 (m, 5H), 3.08-2.98 (m, 3H), 2.85-2.78 (m, 1H), 2.54 (dd,J=15.0, 8.2, 1H), 2.17-2.13 (m, 1H), 1.88-1.83 (m, 1H).

Example 104

(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₄ClN₅O₃, 477.95; m/z found,478.1 [M+H]⁺, 500.1 [M+Na]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09 (s, 1H), 8.76(d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 7.18 (d, J=9.1, 1H), 6.92 (s, 1H),6.92 (s, 1H), 6.89 (s, 1H), 4.23 (s, 4H), 4.11 (s, 3H), 3.89 (s, 2H),3.06-2.98 (m, 3H), 2.84-2.77 (m, 1H), 2.54 (dd, J=15.3, 8.6, 1H),2.17-2.12 (m, 1H), 1.85-1.80 (m, 1H).

Example 105

N-((6-chlorobenzo[d][1,3]dioxol-5-yl)methyl)-2-(6-methoxy-1,5-naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine

MS (ESI): exact mass calculated for C₂₄H₂₂ClN₅O₃, 463.93; m/z found,464.2 [M+H]⁺, 500.1 [M+Na]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10 (s, 1H), 8.76(d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.18 (d,J=9.1, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 5.96 (s, 2H), 4.11 (s, 2H), 3.90(s, 3H), 3.07-2.98 (m, 3H), 2.85-2.78 (m, 1H), 2.54 (dd, J=15.3, 8.5,1H), 2.17-2.14 (m, 1H), 1.88-1.81 (m, 1H).

Example 106

(7-Fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-quinolin-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₆H₂₆FN₅OS, 475.58; m/z found,476.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 8.74 (d, J=4.8, 1H), 8.01 (d,J=9.3, 1H), 7.94 (s, 1H), 7.70 (d, J=2.8, 1H), 7.50-7.48 (m, 2H), 6.66(d, J=10.2, 1H), 6.56 (d, J=6.7, 1H), 3.89 (s, 3H), 3.80 (s, 2H),3.52-3.50 (m, 2H), 3.09-2.94 (m, 5H), 2.79 (ddd, J=16.6, 10.8, 5.8, 1H),2.51 (dd, J=14.9, 8.8, 1H), 2.23-2.20 (m, 1H), 1.84-1.76 (m, 1H).

Example 107

(7-Fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₅H₂₅FN₆OS, 476.57; m/z found,477.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 9.31 (s, 1H), 8.81 (d, J=5.4,1H), 8.33 (d, J=9.2, 1H), 8.27 (d, J=5.4, 1H), 7.41 (d, J=9.2, 1H), 6.84(d, J=10.1, 1H), 6.63 (d, J=6.6, 1H), 4.27 (d, J=5.1, 2H), 4.15 (s, 3H),3.70-3.64 (m, 1H), 3.55-3.53 (m, 2H), 3.42 (dd, J=15.1, 5.0, 1H), 3.10(ddd, J=17.1, 5.4, 3.5, 1H), 3.05-3.04 (m, 2H), 2.94 (ddd, J=17.2, 11.4,5.8, 1H), 2.85 (dd, J=15.1, 10.3, 1H), 2.51-2.48 (m, 1H), 2.09-2.01 (m,1H).

The compounds in Examples 108-120 were prepared according to the methodsdescribed for Example 1.

Example 108

5,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₁F₂N₅O₃S, 521.1; m/z found, 522[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.80 (d, J=9.2,1H), 7.69 (br s, 2H), 7.63 (d, J=2.7, 1H), 7.44 (dd, J=9.2, 2.8, 1H),7.34 (d, J=4.7, 1H), 6.96 (dd, J=9.0, 1.8, 1H), 6.05 (d, J=7.9, 1H),4.67-4.56 (m, 1H), 3.91 (s, 3H), 3.48 (s, 2H), 3.23 (dd, J=15.7, 5.0,1H), 3.08-2.95 (m, 2H), 2.72 (dd, J=15.8, 7.7, 1H), 2.29-2.20 (m, 1H),2.20-2.10 (m, 1H). HPLC (reverse phase, Waters Xterra RP18 5μ column,4.6×100 mm, 1% to 99% acetonitrile in water with 20 mM NH₄OH gradientelution, 1.5 mL/min): R_(T)=4.50 min.

Example 109

5,7-Difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₀F₂N₆O₃S, 522.1; m/z found, 523[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.17 (s, 1H), 8.78 (d, J=5.0, 1H), 8.27(d, J=9.1, 1H), 8.17 (d, J=5.0, 1H), 7.75-7.68 (m, 1H), 7.20 (d, J=9.1,1H), 6.94 (dd, J=8.9, 1.7, 1H), 6.07 (d, J=7.4, 1H), 4.66-4.57 (m, 1H),4.10 (s, 3H), 3.46 (s, 2H), 3.22 (dd, J=15.8, 5.0, 1H), 3.09-2.92 (m,2H), 2.72 (dd, J=15.8, 7.1, 1H), 2.30-2.08 (m, 2H). HPLC (reverse phase,Waters Xterra RP18 5μ column, 4.6×100 mm, 1% to 99% acetonitrile inwater with 20 mM NH₄OH gradient elution, 1.5 mL/min): R_(T)=4.64 min.

Example 110

N-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-methyl-3-nitro-benzamide

MS (ESI): exact mass calculated for C₂₄H₂₂N₆O₄, 458.17; m/z found, 459.1[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.20 (s, 1H), 8.79 (d, J=5.1, 1H), 8.33(d, J=1.6, 1H), 8.28 (d, J=9.1, 1H), 8.19 (d, J=5.0, 1H), 7.95 (d,J=9.6, 1H), 7.45 (d, J=8.1, 1H), 7.21 (d, J=9.1, 1H), 6.22 (d, J=7.2,1H), 4.62-4.56 (m, 1H), 4.11 (s, 3H), 3.26 (dd, J=15.3, 4.9, 1H), 3.03(dd, J=7.8, 7.8, 2H), 2.73 (dd, J=15.3, 7.6, 1H), 2.66 (s, 3H),2.28-2.23 (m, 1H), 2.16-2.10 (m, 1H).

Example 111

N-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-methyl-3-nitro-benzamide

MS (ESI): exact mass calculated for C₂₅H₂₃N₅O₄, 457.18; m/z found, 458.1[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.35 (d, J=1.6,1H), 8.08 (d, J=9.2, 1H), 7.98 (d, J=9.6, 1H), 7.70 (s, 1H), 7.65 (d,J=2.7, 1H), 7.46 (d, J=8.0, 1H), 7.44 (dd, J=9.2, 2.8, 1H), 7.36 (d,J=4.7, 1H), 6.29 (d, J=7.8, 1H), 4.61-4.56 (m, 1H), 3.92 (s, 3H), 3.26(dd, J=15.4, 5.0, 1H), 3.04 (dd, J=6.9, 6.9, 2H), 2.72 (dd, J=15.4, 8.3,1H), 2.67 (s, 3H), 2.31-2.26 (m, 1H), 2.14-2.08 (m, 1H).

Example 112

3-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₁F₃N₆O₃S, 554.13; m/z found,555.1 [M+H]⁺. ¹H NMR (600 MHz, DMF-d₇): 9.30 (s, 1H), 8.86 (d, J=5.0,1H), 8.58 (d, J=7.7, 1H), 8.38 (d, J=9.1, 1H), 8.22 (d, J=5.0, 1H), 7.77(s, 1H), 7.39 (d, J=9.1, 1H), 7.25 (s, 1H), 4.35-4.29 (m, 1H), 4.17 (s,3H), 3.74-3.69 (m, 1H), 3.68 (s, 2H), 3.16 (dd, J=15.3, 5.3, 1H),3.06-2.98 (m, 1H), 2.96-2.88 (m, 2H), 2.25-2.17 (m, 1H), 2.06-1.97 (m,1H).

Example 113

7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₁BrN₆O₃S, 565.44; m/z found,566.4 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.16 (s, 1H), 8.78 (d, J=5.0,1H), 8.27 (d, J=9.0, 1H), 8.16 (d, J=5.0, 1H), 7.82 (s, 1H), 7.52 (s,1H), 7.19 (d, J=9.0, 1H), 7.16 (s, 1H), 6.31 (d, J=8.5, 1H), 4.62-4.56(m, 1H), 4.09 (s, 3H), 3.42 (s, 2H), 3.20 (dd, J=15.5, 5.1, 1H), 3.01(dd, J=6.6, 6.6, 2H), 2.76 (dd, J=15.0, 6.7, 1H), 2.27-2.18 (m, 1H),2.17-2.10 (m, 1H).

Example 114

7-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₂BrN₅O₃S, 564.45; m/z found,565.4 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 10.75 (s, 1H), 8.79 (d, J=4.7,1H), 8.63 (d, J=7.6, 1H), 8.20 (s, 1H), 8.03 (d, J=9.2, 1H), 7.87 (d,J=2.8, 1H), 7.64 (s, 1H), 7.54 (d, J=4.8, 1H), 7.51 (dd, J=9.2, 2.8,1H), 6.96 (s, 1H), 4.22-4.16 (m, 1H), 3.87 (s, 3H), 3.51 (s, 2H), 3.03(dd, J=15.4, 5.2, 1H), 2.98-2.93 (m, 1H), 2.87-2.82 (m, 1H), 2.62 (dd,J=15.7, 9.1, 1H), 2.13-2.10 (m, 1H), 1.93-1.87 (m, 1H).

Example 115

3-Oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₂₂F₃N₅O₃S, 553.14; m/z found,554.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.30 (br s,1H), 8.08 (d, J=9.2, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.61 (d, J=2.8,1H), 7.43 (dd, J=9.2, 2.8, 1H), 7.34 (d, J=4.7, 1H), 7.08 (s, 1H), 5.95(d, J=8.2, 1H), 4.61-4.56 (m, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.20 (dd,J=15.7, 4.9, 1H), 3.07-2.95 (m, 2H), 2.71 (dd, J=15.5, 7.7, 1H),2.27-2.22 (m, 1H), 2.13-2.05 (m, 1H).

Example 116

3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₃N₅O₄, 469.18; m/z found, 470.2[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.80 (d, J=4.7, 1H), 8.61 (br s, 1H),8.08 (d, J=9.2, 1H), 7.70 (s, 1H), 7.66 (d, J=2.7, 1H), 7.58 (d, J=1.3,1H), 7.44 (dd, J=9.2, 2.1, 1H), 7.36 (d, J=4.7, 1H), 7.29 (dd, J=8.4,2.0, 1H), 6.99 (d, J=8.3, 1H), 6.21 (d, J=7.8, 1H), 4.67 (s, 2H),4.65-4.58 (m, 1H), 3.92 (s, 3H), 3.25 (dd, J=15.5, 5.0, 1H), 3.09-2.99(m, 2H), 2.71 (dd, J=15.5, 7.8, 1H), 2.29-2.23 (m, 1H), 2.14-2.07 (m,1H).

Example 117

3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₂N₆O₄, 470.17; m/z found, 471.1[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.20 (s, 1H), 8.79 (d, J=5.1, 1H), 8.28(d, J=9.9, 1H), 8.19 (d, J=5.0, 1H), 7.95 (br s, 1H), 7.44-7.43 (m, 1H),7.30-7.27 (m, 1H), 7.21 (d, J=9.8, 1H), 6.99 (d, J=8.3, 1H), 6.14 (d,J=8.0, 1H), 4.67 (s, 2H), 4.62-4.56 (m, 1H), 4.10 (s, 3H), 3.24 (dd,J=15.1, 5.2, 1H), 3.06-2.95 (m, 2H), 2.72 (dd, J=15.5, 7.5, 1H),2.26-2.19 (m, 1H), 2.16-2.08 (m, 1H).

Example 118

2-Fluoro-N-[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-4-nitro-benzamide

MS (ESI): exact mass calculated for C₂₄H₂₀FN₅O₄, 461.15; m/z found,462.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.81 (d, J=4.7, 1H), 8.33 (dd,J=8.12, 8.12, 1H), 8.19 (dd, J=8.6, 2.1, 1H), 8.09 (d, J=9.2, 1H), 8.02(dd, J=11.1, 2.1, 1H), 7.70 (s, 1H), 7.64 (d, J=2.8, 1H), 7.44 (dd,J=9.2, 2.8, 1H), 7.36 (d, J=4.7, 1H), 6.83-6.80 (m, 1H), 4.66-4.60 (m,1H), 3.92 (s, 3H), 3.26 (dd, J=15.6, 5.1, 1H), 3.06-3.03 (m, 2H), 2.75(dd, J=15.5, 7.9, 1H), 2.32-2.27 (m, 1H), 2.16-2.10 (m, 1H).

Example 119

4-Methoxy-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-nitro-benzamide

MS (ESI): exact mass calculated for C₂₄H₂₂N₆O₅, 474.17; m/z found, 475.1[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 9.17 (s, 1H), 8.78 (d, J=5.0, 1H), 8.27(d, J=9.1, 1H), 8.24 (d, J=2.3, 1H), 8.17 (d, J=5.0, 1H), 8.06 (dd,J=8.8, 2.3, 1H), 7.19 (d, J=9.1, 1H), 7.14 (d, J=8.8, 1H), 6.27 (d,J=7.6, 1H), 4.59-4.54 (m, 1H), 4.09 (s, 3H), 4.01 (s, 3H), 3.24 (dd,J=15.4, 5.1, 1H), 3.01 (dd, J=6.6, 6.6, 2H), 2.72 (dd, J=15.4, 7.7, 1H),2.26-2.21 (m, 1H), 2.13-2.09 (m, 1H).

Example 120

3-(2,4-Difluoro-phenyl)-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-acrylamide

MS (ESI): exact mass calculated for C₂₆H₂₂F₂N₄O₂, 461.17; m/z found462.3, [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.09 (s, 1H), 8.72 (d, J=5.1,1H), 8.23 (d, J=9.1, 1H), 8.11 (d, J=5.1, 1H), 7.62 (d, J=15.8, 1H),7.45-7.41 (m, 1H), 7.17 (d, J=9.1, 1H), 6.87-6.78 (m, 2H), 6.49 (d,J=15.8, 1H), 6.26 (d, J=7.0, 1H), 4.51-4.48 (m, 1H), 4.05 (s, 3H), 3.12(dd, J=15.5, 5.0, 1H), 2.95-2.85 (m, 2H), 2.62 (dd, J=15.6, 7.2, 1H),2.16-2.03 (m, 2H).

Example 121

[2-(3,5-Difluoro-phenoxy)-ethyl]-{2-[1-(6-methoxy-quinolin-4-yl)-1H-pyrazol-4-yl]-1-methyl-ethyl}-amine

To a solution of2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine(160 mg, 0.54 mmol) in DMF (3 mL) was added1-(2-bromo-ethoxy)-3,5-difluoro-benzene (154 mg, 0.65 mmol), Cs₂CO₃ (267mg, 0.82 mmol) and catalytic NaI (25 mg, 0.002 mmol). After 48 h at 50°C., the mixture was concentrated, and the residue was dissolved inEtOAc, washed with H₂O, dried (MgSO₄), and concentrated. The resultingresidue was purified by basic reverse phase HPLC to provide 53.8 mg(29%) of the title compound as a brown gum. MS (ESI): exact masscalculated for C₂₅H₂₄F₂N₄O₂, 450.48; m/z found, 451.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): 8.74 (d, J=4.9, 1H), 8.01 (d, J=9.2, 1H), 7.95 (s,1H), 7.71 (d, J=2.7 1H), 7.50-7.48 (m, 2H), 6.61 (dd, J=9.2, 2.1, 2H),6.52 (tt, J=9.2, 2.2, 1H), 4.14 (t, J=5.3, 2H), 3.90 (s, 3H), 3.13-3.09(m, 4H), 3.00-2.96 (m, 1H), 2.83 (ddd, J=16.6, 10.7, 5.8, 1H), 2.54-2.51(m, 1H), 2.26-2.23 (m, 1H), 1.85-1.77 (m, 1H).

The compounds in Examples 122-123 were prepared according to the methodsdescribed in Example 58.

Example 122

2-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide

MS (ESI): exact mass calculated for C₂₅H₂₃F₃N₆O₂, 496.18; m/z found,497.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.37 (s, 1H), 9.09 (s, 1H), 8.79(d, J=5.0, 1H), 8.24 (d, J=7.8, 1H), 8.2 (d, J=5.0, 1H), 7.82 (br s,1H), 7.38 (d, J=8.0, 1H), 7.15 (d, J=9.0, 1H), 7.11-7.02 (m, 2H), 3.88(s, 3H), 3.62 (d, J=17.8, 1H), 3.43 (d, J=17.8, 1H), 3.29-3.20 (m, 1H),3.11-3.04 (m, 1H), 2.96-2.89 (m, 2H), 2.64 (dd, J=15.7, 9.0, 1H),2.17-2.13 (m, 1H), 2.03-1.97 (m, 1H).

Example 123

N-(3-Chloro-phenyl)-2-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-acetamide

MS (ESI): exact mass calculated for C₂₄H₂₃ClN₆O₂, 462.16; m/z found,463.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.22 (s, 1H), 9.09 (s, 1H), 8.78(d, J=5.0, 1H), 8.25 (d, J=9.1, 1H), 8.21 (d, J=5.0, 1H), 7.37 (t,J=1.8, 1H), 7.20-7.18 (m, 1H), 7.16 (d, J=9.0, 1H), 6.89 (t, J=8.0, 1H),6.80-6.78 (m, 1H), 3.88 (s, 3H), 3.62 (d, J=17.5, 1H), 3.37 (d, J=17.5,1H), 3.27-3.25 (m, 1H), 3.10-3.05 (m, 1H), 2.94-2.86 (m, 2H), 2.65 (dd,J=15.8, 5.6, 1H), 2.14-2.11 (m, 1H), 2.02-1.99 (m, 1H).

The compounds in Examples 124-134 were prepared according to the methodsdescribed in the preceding examples.

Example 124

5-Acetylamino-2-bromo-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-benzamide

MS (ESI): exact mass calculated for C₂₅H₂₃BrN₆O₃, 534.10; m/z found,535.1 [M+H]⁺.

Example 125

2,4-Dichloro-5-fluoro-N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-benzamide

MS (ESI): exact mass calculated for C₂₃H₁₈Cl₂FN₅O₂, 485.08; m/z found,486.1 [M+H]⁺.

Example 126

6-Dimethylamino-2-fluoro-3-{[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-benzonitrile

MS (ESI): exact mass calculated for C₂₇H₂₇FN₆O, 470.22; m/z found, 471.2[M+H]⁺.

Example 127

8-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₅H₂₂FN₅O₄, 475.17; m/z found,476.2 [M+H]⁺.

Example 128

8-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₃FN₄O₄, 474.17; m/z found,475.2 [M+H]⁺.

Example 129

2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₈H₂₇N₅O₃S, 513.18; m/z found,514.2 [M+H]⁺.

Example 130

7-Methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₄N₆O₄S, 516.16; m/z found,517.2 [M+H]⁺.

Example 131

7-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₂₅N₅O₃S, 499.17; m/z found,500.2 [M+H]⁺.

Example 132

7-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[1-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₇H₂₅N₅O₃S, 499.17; m/z found,500.2 [M+H]⁺.

Example 133

7-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide

MS (ESI): exact mass calculated for C₂₆H₂₄N₆O₃S, 500.16; m/z found,501.2 [M+H]⁺.

Example 134

[2-(3,5-Difluoro-phenoxy)-ethyl]-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amine

MS (ESI): exact mass calculated for C₂₄H₂₃F₂N₅O₂, 451.18; m/z found,452.2 [M+H]⁺.

Example 135

6-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylicacid ethyl ester

A. 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6,7-dicarboxylic acid 7-ethylester 6-methyl ester. The title compound was prepared as described inExample H. MS (ESI): exact mass calculated for C₁₃H₁₃NO₅S, 295.05; m/zfound, 296.1 [M+H]⁺.

B. 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6,7-dicarboxylic acid 7-ethylester. To a slurry of potassium trimethyl silanolate (16 mg, 0.125 mmol)in dry CH₂Cl₂ (0.78 mL) was added3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6,7-dicarboxylic acid 7-ethylester 6-methyl ester (37 mg, 0.125 mmol), and the mixture was stirred atrt under a nitrogen atmosphere for 3 h. The mixture was diluted with 1 NHCl (20 mL), and extracted with EtOAc (1×20 mL). The organic layer waswashed with H₂O (2×20 mL) and satd. aq. NaCl (1×20 mL), then dried(Na₂SO₄), filtered, and concentrated to afford the title compound, whichwas used without further purification. MS (ESI): exact mass calculatedfor C₁₂H₁₁NO₅S, 281.04; m/z found, 282.0 [M+H]⁺.

C. The title compound was prepared as described in the precedingexamples. MS (ESI): exact mass calculated for C₂₉H₂₇N₅O₅S, 557.17; m/zfound, 558.2 [M+H]⁺.

Example 136

6-[2-(6-Methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylicacid, Potassium Salt

To a solution of6-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylicacid ethyl ester (5.9 mg, 0.011 mmol) in isopropanol (0.5 mL) was addedKOH (0.21 M in H₂O; 50 μL, 1 eq. KOH). After stirring at rt for 3 h themixture was concentrated, redissolved in warm acetonitrile, and cooledto −78° C. The resulting frozen sample was dried on a lyophilizer toafford 5.8 mg (100%) of the title compound as the potassium carboxylatesalt. MS (ESI): exact mass calculated for C₂₇H₂₃N₅O₅S, 529.14; m/zfound, 530.1 [M+H]⁺.

Example 137

6-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylicacid ethyl ester

The title compound was prepared as described in Example 135. MS (ESI):exact mass calculated for C₂₅H₂₆N₆O₅S, 558.17; m/z found, 559.2 [M+H]⁺.

Example 138

6-[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylcarbamoyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-7-carboxylicacid

The title compound was prepared as described in Example 136. MS (ESI):exact mass calculated for C₂₆H₂₂N₆O₅S, 530.14; m/z found, 531.1 [M+H]⁺.

Example 139

6-{[1-(2-Trifluoromethyl-quinolin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one

MS (ESI): exact mass calculated for C₂₆H₂₂F₃N₅OS, 509.15; m/z found,510.8 [M+H]⁺.

Embodiments of compounds according to the present invention comprisestructural elements with the framework (FM)

Additional illustrative embodiments of this invention are provided bycombinations of substituents in (FM) and in combinations of assignmentsfor B¹, B⁵, B⁸, n, m, and X, as well as for the N1 or N2 bonding, thatare not explicitly listed herein, but that one of ordinary skill in theart would be able to prepare in light of the teachings provided herein.

Further examples of embodiments of this invention are provided by salt,ester and amide forms of compounds exemplified herein and equivalentsthereof. By way of illustration, the carboxylic group in compounds suchas Example 68 can form salts, preferably pharmaceutically acceptablesalts; the basic nitrogen member in compounds such as Examples 1-99 canform salts, preferably pharmaceutically acceptable salts; and thecarboxylic acid group in compounds such as Example 68 can form amides,wherein such salts, esters and amides are formed by methods known in theart.

Assay Methods

Assay results provided herein are illustrative results of the assaysthat were performed for compounds of this invention.

Biological Example 1 In Vitro Antibacterial Activity (MIC Assay)

Minimal inhibitory concentration (MIC) has been an indicator of in vitroantibacterial activity widely used in the art. The in vitroantibacterial activity of the compounds was determined by the brothmicrodilution method described by the National Committee for ClinicalLaboratory Standards (NCCLS) in the NCCLS Document M7-A5, Vol. 20, No.2, “Methods for Dilution Antimicrobial Susceptibility Test for Bacteriathat Grow Aerobically—Fifth Edition”, which is incorporated herein byreference.

In this method, an aliquot of test compound from an 11-point series of2-fold serial dilutions of compounds in 100% DMSO was added to wells inmicrodilution plates. The test organisms were prepared by adjusting theturbidity of actively growing broth cultures so that the finalconcentration of test organism after addition to wells with or withoutcompounds was approximately 5×10⁵ CFU/mL.

Following inoculation of the microdilution plates, the plates wereincubated at 35° C. for 16-24 h and then scored for bacterial growth.The MIC is defined as the lowest concentration of test compound thatcompletely inhibits the visible growth of the test organism. The amountof growth in the wells containing the test compound was compared withthe amount of growth in the growth-control wells (no test compound used)in each plate, and with the amount of growth in the wells containingcontrol compounds (such as ciprofloxacin). Compounds of the presentinvention were tested against several bacterial strains. The MIC values(in μg/mL) are presented in Table 1 for Gram-negative (E. coli KL-16(GSC strain 4245); data marked as (*) was obtained with E. coliATCC25922) and Gram-positive bacteria (S. aureus ATCC13709; S.pneumoniae ATCC49619).

Biological Example 2 DNA Gyrase Inhibition Assay

Inhibition of the supercoiling activity of E. coli DNA gyrase wasdetermined using enzymes, buffers and substrates received from JohnInnes Enterprises Ltd. (John Innes Centre, UK). The reactions wereperformed according to the manufacturer's directions, with the followingmodifications.

DNA supercoiling reactions were carried out in a total reaction volumeof 20 μL containing 250 ng of relaxed pBR322, 35 mM Tris-HCl (pH 7.5),24 mM KCl, 4 mM MgCl₂, 2 mM dithiothreitol, 1.8 mM spermidine, 1 mM ATP,6.5% glycerol and 100 μg/mL albumin. Compounds diluted in 10% DMSO wereadded to the reaction mixture to reach a final concentration of 0.5%DMSO. Enzyme was diluted to 0.08 unit/4 in a solution of 50 mM Tris-HCl(pH 7.5), 100 mM KCl, 2 mM dithiothreitol, 1 mM EDTA, and 50% glycerol.Diluted enzyme (0.2 unit) was added to each reaction.

The reactions were incubated at 37° C. for 30 min. The reactions werethen cooled to 0° C., followed by addition of 3 μL of 40% glycerol, 100mM Tris-HCl (pH 7.5), 50 mM EDTA, 0.5% SDS and 0.1% bromophenol blue.Samples were separated on 1.0% agarose gels. Gels were stained withEthidium bromide and photographed with a Stratagene Eagle Eye II. IC₅₀values (in μg/mL) were determined by visual inspection of thephotographs, and are listed in Table 1.

TABLE 1 S. aureus S. pneumoniae E. coli KL-16 ATCC13709 ATCC49619 DNAGyrase Ex. MIC (μg/mL) MIC (μg/mL) MIC (μg/mL) IC₅₀ 1 >128 0.5 8 >322 >128 0.5 8 16 3 >128 1 4 4 4 >128 0.06 4 0.25 5   128 0.25 2 0.12 6   2 <0.125 4 0.12 7 >128 0.25 >128 2 8 >128 0.25 4 >16 9 >128 0.254 >16 10 >128 0.25 2 8 11 >128 <0.125 16 2 12 >128 0.25 8 2 13 >128 0.58 >16 14 >128 1 16 1 15 >128 1 16 >32 16 >128 2 8 4 17    4 0.25 2 0.1218    4 0.03 1 8 19 >128 0.5 8 >32 20    2 <0.125 2 0.5 21 >128 1 8 >1622 >128 0.5 8 0.5 23 >128 <0.125 2 4 24 >128 <0.125 4 16 25 >128 1 8 >1626 >128 0.25 2 >16 27    4 0.125 4 4 28    16 0.25 4 2 29 >128 1 4 1630 >128 1 8 16 31    16 0.25 4 2 32    16 0.25 4 16 33 >128 1 8 234 >128 0.5 8 2 35 >128 <0.125 1 2 36    8 <0.125 0.25 0.5 37    32 0.52 0.25 38 >128 0.25 4 2 39 >128 0.5 1 4 40    4 0.25 4 2 41    2 0.25 20.06 42    32 0.03 0.5 1 43    16 >0.125 1 0.5 44    2 0.5 2 <0.125 45  128 0.25 <0.125 0.8 46    16 0.06 <0.125 0.12 47   128 1 4 2 48    320.25 1 >32 49   128 <0.125 0.5 3 50   128 0.5 1 2 51 >128 1 1 4 52    20.25 1 0.125 53    4 0.25 2 0.5 54    2 1 2 0.06 55    64 0.5 1 4 56  128 1 2 4 57    64 1 2 2 58    16 0.25 4 1 59   128 1 8 16 60 >128 18 >16 61    16 0.5 8 2 62 >128 1 16 4 63    6 0.1 0.8 4 64    64 4128 >4 65 >128 0.5 1 1 66 >128 8 >128 2 67 >128 4 64 >8 68 >128 8 8 169 >128 4 64 >4 70 >128 2 32 >32 71 >128 2 8 16 72 >128 2 >128 >1673 >128 4 64 >16 74 >128 1 8 2 75 >128 4 16 >16 76 >128 2 >128 1677 >128 2 16 >16 78 >128 16 >128 >16 79 >128 4 8 >16 80 >128 8 128 >1681 >128 2 >128 16 82 >128 8 >128 4 83 >128 2 32 <0.25 84 >128 2 16 8 85   64 8 8 2 86 >128 4 4 2 87    64 2 8 2 88 >128 4 8 NT 89    16 2 20.125 90 >128 0.5 >128 >16 91 >128 4 >128 >16 92 >128 0.5 >128 >1693 >128 0.25 16 >16 94 >128 2 >128 4 95 >128 2 8 >16 96    64 8 32 >497 >128 >128 >128 >16 98 >128 16 64 NT 99 >128 2 >128 8 100    16 0.250.5 0.5 101    4 0.125 1 0.25 102    8 0.5 0.5 0.5 103    32 0.5 4 2 104   8 0.125 1 0.5 105 >128 0.5 4 2 106    8 0.5 1 2 107     8* 0.25 2 NT108    8 0.125 1 1 109 >128 0.125 4 1 110 >128 0.25 8 NT 111 >128 0.254 >16 112    4 0.125 8 0.25 113    2 0.125 2 0.25 114    2 0.125 2 0.5115    8 0.125 8 1 116    2 0.125 4 0.25 117    4 0.125 8 1 118 >1284 >128 >16 119 >128 4 8 NT 120 >128 0.125 4 2 121    8 1 2 0.5 122 >1282 32 4 123 >128 1 >128 4 124 >128 4 >128 NT 125 >128 0.25 8 NT 126 >1281 2 NT 127 >128 0.5 8 NT 128 >128 2 8 NT 129  >16* 1 4 NT 130  >16* 2 16NT 131    8 0.5 16 NT 132  >16* 2 >16 NT 133  >16* 0.25 >16 NT 134  >16*1 4 NT 135  >16* 2 >16 NT 136  >16* 1 >16 NT 137  >16* 0.5 >16 NT 138 >16* 0.5 16 NT 139 >128 8 32 >16 NT = not tested

Biological Example 3 Topoisomerase IV Inhibition Assay

Inhibition of the relaxation activity of E. coli topoisomerase IV wasdetermined using enzyme, buffers and substrates received from John InnesEnterprises Ltd. (John Innes Centre, UK). The reactions were performedaccording to the manufacturer's directions, with the followingmodifications.

DNA relaxation reactions were carried out in a total reaction volume of20 μL, containing 300 ng of supercoiled pBR322, 40 mM HEPES-KOH (pH7.6), 100 mM potassium glutamate, 10 mM Mg(OAc)₂, 10 mM DTT, 4 μg/mLtRNA, 2 mM ATP, and 50 μg/mL BSA. Compounds, diluted in 10% DMSO, wereadded to the reaction mixture to reach a final concentration of 0.5%DMSO. Enzyme was diluted to 0.45 unit/4 in a solution of 40 mM HEPES-KOH(pH 7.6), 150 mM potassium glutamate, 1 mM DTT, 1 mM EDTA, and 40%glycerol. Diluted enzyme (0.9 unit) was added to each reaction.

The reactions were incubated at 37° C. for 45 min. The reactions werethen cooled to 0° C. followed by addition of 3 μL of 40% glycerol, 100mM Tris-HCl (pH 7.5), 50 mM EDTA, 0.5% SDS and 0.1% bromophenol blue.Samples were separated on 1.0% agarose gels. Gels were stained withEthidium bromide and photographed with a Stratagene Eagle Eye II. IC₅₀values (in μg/mL) were determined by visual inspection of thephotographs, and are listed in Table 2.

TABLE 2 Topoisomerase IV Topoisomerase IV Ex. IC₅₀ Ex. IC₅₀ 1 >1 410.016 3 1 42 0.25 4 0.25 44 0.016 5 0.125 46 <0.015 17 0.125 50 0.06 180.25 52 0.03 21 1 53 0.016 23 >1 54 0.016 25 1 58 0.016 27 0.5 64 0.2528 0.5 68 0.5 29 0.5 69 0.5 31 0.125 70 >1 32 0.125 80 >1 33 1 81 >0.534 0.125 82 0.5 36 0.03 83 0.25 37 0.25 86 1 38 0.25 87 0.5 39 0.5 890.015 40 0.06 115 0.25 102 0.0625 116 0.5 103 0.25 117 0.25 113 0.25 1210.125 114 0.125

Biological Example 4 Resistant Strains Assays

Compounds of the present invention were tested for activity againstsusceptible and resistant bacterial strains in vitro, and activity wascompared to known anti-bacterial agents. Testing protocols followedNCCLS methodology for broth microdilution assays. MIC values in μg/mLare presented in Table 3 for the following strains: Column A: MSSAATCC13709 (Smith); Column B: MSSA ATCC 29213; Column C: MRSA OC3726(COL); Column D: MRSA OC2878.

TABLE 3 Ex. or Name A B C D Ciprofloxacin 0.25-0.5 0.25-0.5 0.5-1 0.5Norfloxacin 1 2 2 1 Sparfloxacin 0.062 0.062 0.125 0.062 4 0.06 1 0.0620.031 5 0.25 0.031 0.062 0.031 17 0.25 0.062 0.125 0.125 18 0.031 0.250.062 0.062 31 0.25 16 0.5 0.25 41 0.25 0.25 1 0.5 46 0.062 8 0.25 0.12550 0.5 16 1 0.5 52 0.25 1 0.5 0.5 55 0.5 2 1 0.5

MIC values in μg/mL are presented in Table 4 for the following strains:Column E: CipR MRSA OC3946; Column F: CipR MRSA OC4159; Column G: CipRMRSA OC4222; Column H: CipR MRSA OC5273.

TABLE 4 Ex. or Name E F G H Ciprofloxacin 16 128 64 128 Norfloxacin128 >128 >128 >128 Sparfloxacin 4 16 8 16 4 0.007 0.5 0.5 0.062 5 0.0070.007 0.015 0.031 17 0.015 0.031 0.062 0.25 18 0.015 0.031 0.031 0.06231 0.125 4 4 0.5 41 0.25 0.25 0.25 0.5 46 0.062 0.062 0.062 0.125 50 0.516 16 1 52 0.125 0.25 0.125 0.5 55 0.5 0.5 0.25 1

Additional data obtained for CipR MRSA OC4222 is shown in Table 4A.

TABLE 4A Ex. or Name G 107 0.5 108 0.06 109 0.03 129 1 130 2 131 0.5 1322 133 0.25 134 0.5 135 2 136 2 137 0.5 138 0.5

References cited in the specification are incorporated herein byreference. Having described the invention in specific detail andexemplified the manner in which it may be carried into practice, it willbe apparent to those skilled in the art that innumerable variations,applications, modifications, and extensions of the basic principlesinvolved may be made without departing from its spirit or scope. It isto be understood that the foregoing is merely exemplary and the presentinvention is not to be limited to the specific form or arrangements ofparts herein described and shown.

1. A compound of formula (I):

where said formula (I) has a B-containing bicyclic ring system

and a fused pyrazole moiety

wherein each of B¹, B⁵, and B⁵ is CR^(a); each of R^(a), R², R³, R⁶ andR⁷ is independently selected from the group consisting of —H,—C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C₃₋₆cycloalkyl, —OR^(b),—NR^(c)R^(d), —O(CH₂)₂₋₃NR^(c)R^(d), —SR^(b), —S(O)R^(b), —SO₂R^(b),cyano, —CF₃, halo, —NO₂, —OCF₃, —C(O)R^(b), —OC(O)R^(b),—C(O)NR^(c)R^(d), and —CO₂R^(b); wherein each of R^(b), R^(c) and R^(d)is independently selected from the group consisting of —H, —C₁₋₄alkyl,—C₃₋₆cycloalkyl, and —C₁₋₂alkyl(C₃₋₆cycloalkyl)-; and wherein each alkylor cycloalkyl moiety in any of R^(a), R², R³, R⁶, R⁷, R^(b), R^(c), andR^(d) is optionally and independently substituted with one, two or threesubstituents selected from —C₁₋₃alkyl, halo, hydroxy, amino, and—C₁₋₃alkoxy; the B-containing bicyclic ring system is attached at the 1-or 2-position of the fused pyrazole moiety; m is 0 or 1; n is 1 or 2,wherein m+n is 2 or 3; X is CH or N; provided that when X is N, then Yis —C(O)—, —CH₂C(O)—, or —(CH₂)₂₋₃O—optionally substituted with—C₁₋₃alkyl; and when X is CH, then Y is —N(R^(e))Z—; Z is selected fromthe group consisting of: C₁₋₃alkylene optionally substituted with—C₁₋₃alkyl; C₃alkenylene optionally substituted with —C₁₋₃alkyl;—C(O)C₂alkenyl- optionally substituted with —C₁₋₃alkyl; —(CH₂)₀₋₁C(O)—;—CH₂C(O)N(R^(f))(CH₂)₀₋₁—; —(CH₂)₂₋₃O—; and —C(O)C(R^(g1))(R^(g2))—;where R^(e) is —H, —C₁₋₄alkyl, benzyl, —C(O)C₁₋₆alkyl, —C(O)phenyl,—C(O)benzyl, —C₁₋₆alkylCO₂C₁₋₆alkyl, or —C₁₋₆alkylCO₂H; R^(f) is —H or—C₁₋₄alkyl; and each of R^(g1) and R^(g2) is independently —H or methyl,or R^(g1) and R^(g2) are taken together with their carbon of attachmentto form a C₃₋₇cycloalkyl, or the group C(R^(g1))(R^(g2)) is the groupC═O; A is an aryl or heteroaryl ring selected from the group consistingof: a) unsubstituted phenyl, unsubstituted pyridyl, substituted phenyl,and substituted pyridyl, wherein said substituted phenyl is moiety (M1)or moiety (M2)

and said substituted pyridyl is moiety (M3) or moiety (M4)

wherein R^(r)(p-q) stands for a number of R^(r) substituents that is atleast p and does not exceed q, and

 is a disubstituent at two adjacent carbon members, said disubstituentbeing selected from the group consisting of —O—C14AL-O—,—N(R^(h))(CH₂)₂₋₃S—, —N(R^(h))C(O)(CH₂)₁₋₂S—, —N(R^(h))C(O)C(CH₃)₂S—,—N(R^(h))(CH₂)₂₋₃O—, —N(R^(h))C(O)(CH₂)₁₋₂O—, —N(R^(h))(CH₂)₂₋₃NH—, and—N(R^(h))C(O)(CH₂)₁₋₂NH—, wherein said C14AL is a C₁₋₄alkyleneoptionally mono- or di-substituted with F, where each —R^(r) isindependently selected from the group consisting of —OH, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₂₋₆alkenyl, —OC₃₋₆alkenyl, —C₂₋₆alkynyl, —OC₃₋₆alkynyl,—CN, —NO₂, —N(R^(y))R^(z), —C(O)N(R^(y))R^(z), —N(R^(t))C(O)R^(t),—N(R^(t))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —SC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—SO₂N(R^(y))R^(z), halo, —CF₃, —OCF₃, —CO₂H and —CO₂C₁₋₆alkyl; whereinR^(t) is —H or —C₁₋₆alkyl; R^(y) and R^(z) are independently selectedfrom —H and —C₁₋₆alkyl, or R^(y) and R^(z) are taken together with theirnitrogen of attachment to form pyrrolidinyl or piperidinyl; and R^(h) isselected from the group consisting of —H, —C₁₋₆alkyl, —C₁₋₆alkylCO₂H,—C₁₋₆alkylCO₂C₁₋₆alkyl, and benzyl; b) a five-membered monocyclicheteroaromatic group having a carbon member which is the point ofattachment, having one hetero-member that is >O, >S, >NH or>N(C₁₋₄alkyl), having up to one additional hetero-member that is —N═,said five-membered monocyclic heteroaromatic group being optionallymono- or di-substituted with R^(r) and optionally benzofused orpyridofused, where the benzofused or pyridofused moiety is optionallymono-, di-, or tri-substituted with R^(r); and c) a six-memberedmonocyclic heteroaromatic group having a carbon member which is thepoint of attachment, having two hetero-members each being —N═, saidsix-membered monocyclic heteroaromatic group being optionally mono- ordi-substituted with R^(r) and optionally benzofused or pyridofused,where the benzofused or pyridofused moiety is optionally mono- ordi-substituted with R^(r); a stereoisomer, racemate, tautomer,pharmaceutically acceptable salt, ester, or amide thereof.
 2. A compoundof formula (I):

where said formula (I) has a B-containing bicyclic ring system

and a fused pyrazole moiety

wherein each of B¹, B⁵, and B⁸ is CR^(a); each of R^(a), R², R³, R⁶ andR⁷ is independently selected from the group consisting of —H,—C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C₃₋₆cycloalkyl, —OR^(b),—NR^(c)R^(d), —O(CH₂)₂₋₃NR^(c)R^(d), —SR^(b), —S(O)R^(b), —SO₂R^(b),cyano, —CF₃, halo, —NO₂, —OCF₃, —C(O)R^(b), —OC(O)R^(b),—C(O)NR^(c)R^(d), and —CO₂R^(b); wherein each of R^(b), R^(c) and R^(d)is independently selected from the group consisting of —H, —C₁₋₄alkyl,—C₃₋₆cycloalkyl, and —C₁₋₂alkyl(C₃₋₆cycloalkyl)-; and wherein each alkylor cycloalkyl moiety in any of R^(a), R², R³, R⁶, R⁷, R^(b), R^(c), andR^(d) is optionally and independently substituted with one, two or threesubstituents selected from —C₁₋₃alkyl, halo, hydroxy, amino, and—C₁₋₃alkoxy; the B-containing bicyclic ring system is attached at the 1-or 2-position of the fused pyrazole moiety; m is 0 or 1; n is 1 or 2,wherein m+n is 2 or 3; X is CH or N; provided that when X is N, then Yis —C(O)—, —CH₂C(O)—, or —(CH₂)₂₋₃O— optionally substituted with—C₁₋₃alkyl; and when X is CH, then Y is —N(R^(e))Z—; Z is selected fromthe group consisting of: C₁₋₃alkylene optionally substituted with—C₁₋₃alkyl; C₃alkenylene optionally substituted with —C₁₋₃alkyl;—C(O)C₂alkenyl- optionally substituted with —C₁₋₃alkyl; —(CH₂)₀₋₁C(O)—;—CH₂C(O)N(R^(f))(CH₂)₀₋₁—; —(CH₂)₂₋₃O—; and —C(O)C(R^(g1))(R^(g2))—;where R^(e) is —H, —C₁₋₄alkyl, benzyl, —C(O)C₁₋₆alkyl, —C(O)phenyl,—C(O)benzyl, —C₁₋₆alkylCO₂C₁₋₆alkyl, or —C₁₋₆alkylCO₂H; R^(f) is —H or—C₁₋₄alkyl; and each of R^(g1) and R^(g2) is independently —H or methyl,or R^(g1) and R^(g2) are taken together with their carbon of attachmentto form a C₃₋₇cycloalkyl, or the group C(R^(g1))(R^(g2)) is the groupC═O; A is an aryl or heteroaryl ring selected from the group consistingof: a) unsubstituted phenyl, unsubstituted pyridyl, substituted phenyl,and substituted pyridyl, wherein said substituted phenyl is moiety (M1)or moiety (M2)

and said substituted pyridyl is moiety (M3) or moiety (M4)

wherein R^(r)(p-q) stands for a number of R^(r) substituents that is atleast p and does not exceed q, and

 is a disubstituent at two adjacent carbon members, said disubstituentbeing selected from the group consisting of —O—C14AL-O—,—N(R^(h))(CH₂)₂₋₃S—, —N(R^(h))C(O)(CH₂)₁₋₂S—, —N(R^(h))(CH₂)₂₋₃O—,—N(R^(h))C(O)(CH₂)₁₋₂O—, —N(R^(h))(CH₂)₂₋₃NH—, and—N(R^(h))C(O)(CH₂)₁₋₂NH—, wherein said C14AL is a C₁₋₄alkyleneoptionally mono- or di-substituted with F, where each —R^(r) isindependently selected from the group consisting of —OH, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₂₋₆alkenyl, —OC₃₋₆alkenyl, —C₂₋₆alkynyl, —OC₃₋₆alkynyl,—CN, —NO₂, —N(R^(y))R^(z), —C(O)N(R^(y))R^(z), —N(R^(t))C(O)R^(t),—N(R^(t))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —SC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—SO₂N(R^(y))R^(z), halo, —CF₃, —OCF₃, —CO₂H and —CO₂C₁₋₆alkyl; whereinR^(t) is —H or —C₁₋₆alkyl; R^(y) and R^(z) are independently selectedfrom —H and —C₁₋₆alkyl, or R^(y) and R^(z) are taken together with theirnitrogen of attachment to form pyrrolidinyl or piperidinyl; and R^(h) isselected from the group consisting of —H, —C₁₋₆alkyl, —C₁₋₆alkylCO₂H,—C₁₋₆alkylCO₂C₁₋₆alkyl, and benzyl; b) a five-membered monocyclicheteroaromatic group having a carbon member which is the point ofattachment, having one hetero-member that is >O, >S, >NH or>N(C₁₋₄alkyl), having up to one additional hetero-member that is —N═,said five-membered monocyclic heteroaromatic group being optionallymono- or di-substituted with R^(r) and optionally benzofused orpyridofused, where the benzofused or pyridofused moiety is optionallymono-, di-, or tri-substituted with R^(r); and c) a six-memberedmonocyclic heteroaromatic group having a carbon member which is thepoint of attachment, having two hetero-members each being —N═, saidsix-membered monocyclic heteroaromatic group being optionally mono- ordi-substituted with R^(r) and optionally benzofused or pyridofused,where the benzofused or pyridofused moiety is optionally mono- ordi-substituted with R^(r); a stereoisomer, racemate, tautomerpharmaceutically acceptable salt, ester, or amide thereof.
 3. Thecompound of claim 2, wherein each of B¹, B⁵, and B⁸ is CH.
 4. Thecompound of claim 2, wherein R^(a), R², R³, R⁶, and R⁷ are eachindependently selected from —H, —C₁₋₃alkyl, —OC₁₋₃alkyl, halo, or —CF₃.5. The compound of claim 2, wherein R^(a) is —H or —CF₃.
 6. The compoundof claim 2, wherein R² is —H, —CH₃, or —CF₃.
 7. The compound of claim 2,wherein R⁶ is —H, —OC₁₋₃alkyl, or halo.
 8. The compound of claim 2,wherein R⁶ is —OC₁₋₃alkyl.
 9. The compound of claim 2, wherein R⁶ is —H,—OCH₃, or —F.
 10. The compound of claim 2, wherein R⁶ is —OCH₃.
 11. Thecompound of claim 2, wherein R⁷ is —H or —Cl.
 12. The compound of claim2, wherein the B-containing bicyclic ring system is attached at the2-position of the fused pyrazole moiety.
 13. The compound of claim 2,wherein m=n=1.
 14. The compound of claim 2, wherein n is 2 and m is 1.15. The compound of claim 2, wherein X is N.
 16. The compound of claim2, wherein X is CH.
 17. The compound of claim 16, wherein Y is—N(benzyl)CH₂—, —N(CH₂CO₂tBu)CH₂—, —N(CH₂CO₂H)CH₂—, —NHCH₂—, —NH(CH₂)₃—,—NHCH₂CHCH—, —NHCH₂C(Me)CH—, —NHC(O)—, —NHC(O)CHCH—, —NHCH₂C(O)NH—,—NHCH₂C(O)NHCH₂—, —NHCH₂C(O)—, —NHC(O)C(O)—, —NH(CH₂)₂O—, or—NHC(O)C(R^(g1))(R^(g2))—.
 18. The compound of claim 2, wherein X is CH,and Z is one of C₁₋₃alkylene, C₃alkenylene, —C(O)C₂alkenyl-,—(CH₂)₀₋₁C(O)—, —CH₂C(O)N(R^(f))(CH₂)₀₋₁—, —(CH₂)₂₋₃O—, and—C(O)C(R^(g1))(R^(g2))—.
 19. The compound of claim 2, wherein X is CH,R^(e) is —H, and Z is C═O.
 20. The compound of claim 2, wherein A isphenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2-nitrophenyl, 5-fluoro-2-trifluoromethylphenyl,4-dimethylaminophenyl, 4-diethylaminophenyl, 4-piperidin-1-ylphenyl,4-pyrrolidin-1-ylphenyl, 2-fluoro-4,5-dimethoxyphenyl,2-chloro-5-nitrophenyl, 2-fluoro-3-cyano-4-dimethylaminophenyl,pyridin-3-yl, 2-chloro-pyridin-3-yl, or pyridin-2-yl.
 21. The compoundof claim 2, wherein A is 4-methyl-3-nitrophenyl, 2-fluoro-4-nitrophenyl,2,4-difluorophenyl, 3-trifluoromethylphenyl,5-acetylamino-2-bromophenyl, or 2,4-dichloro-5-fluorophenyl.
 22. Thecompound of claim 2, wherein A is 2,3-dihydro-benzo[1,4]dioxin-6-yl,7-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl,3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, benzo[1,3]dioxol-5-yl,2,2-difluoro-benzo[1,3]dioxol-5-yl,3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl, 3-oxo-4H-benzo[1,4]oxazin-6-yl,4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, or4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl.
 23. The compound of claim2, wherein A is 8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl,6-chloro-benzo[1,3]dioxol-5-yl,7-fluoro-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,5,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3-oxo-7-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,7-ethoxycarbonyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, or7-carboxy-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl.
 24. The compoundof claim 2, wherein A is 4,6-difluoro-1H-indol-2-yl,1H-benzimidazol-2-yl, 1H-indol-2-yl, benzo[b]thiophen-2-yl,4-fluoro-benzo[b]thiophen-2-yl, benzofuran-2-yl, thiophen-2-yl,quinoxalin-2-yl, 5-bromo-thiophen-2-yl, 5-acetyl-thiophen-2-yl,5,6-difluoro-1H-indol-2-yl, 5-methyl-1H-indol-2-yl,5-bromo-1H-indol-2-yl, or 5-chloro-1H-indol-2-yl.
 25. A compoundselected from:7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide;3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid(2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-amide; andpharmaceutically acceptable salts thereof.
 26. A pharmaceuticalcomposition comprising at least one compound of claim 1.